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Wikipedia

Paracetamol

February 16, 2024

Paracetamol (acetaminophen[a] or para-hydroxyacetanilide) 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.

Paracetamol
Clinical data
PronunciationParacetamol: /ˌpærəˈsiːtəmɒl/
Acetaminophen: /əˌsiːtəˈmɪnəfɪn/ ⓘ
Trade namesTylenol, Panadol, others[1]
Other namesN-acetyl-para-aminophenol (APAP), acetaminophen (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa681004
License data
Pregnancy
category
Routes of
administration		Oral (by mouth), rectal, intravenous (IV)
Drug classAnalgesics and antipyretics
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63–89%[5]: 73 
Protein bindingnegligible to 10–25% in overdose[6]
MetabolismPredominantly in the liver[9]
MetabolitesAPAP gluc, APAP sulfate, APAP GSH, APAP cys, AM404, NAPQI[7]
Onset of actionPain relief onset by route:
oral – 37 minutes[8]
Intravenous – 8 minutes[8]
Elimination half-life1.9–2.5 hours[6]
ExcretionUrine[6]
Identifiers
  • N-(4-hydroxyphenyl)ethanamide
CAS Number
  • 103-90-2 Y
PubChem CID
  • 1983
PubChem SID
  • 46506142
IUPHAR/BPS
  • 5239
DrugBank
  • DB00316 Y
ChemSpider
  • 1906 Y
UNII
  • 362O9ITL9D
KEGG
  • D00217 Y
  • C06804
ChEBI
  • CHEBI:46195 Y
ChEMBL
  • ChEMBL112 Y
PDB ligand
  • TYL (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID2020006
ECHA InfoCard100.002.870
Chemical and physical data
FormulaC8H9NO2
Molar mass151.165 g·mol−1
3D model (JSmol)
  • Interactive image
Density1.263 g/cm3
Melting point169 °C (336 °F) [10][11]
Solubility in water
  • 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)
  • CC(=O)Nc1ccc(O)cc1
  • InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) Y
  • Key:RZVAJINKPMORJF-UHFFFAOYSA-N Y
  (verify)

At a standard dose, paracetamol only 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 may relieve pain in acute mild migraine but only slightly in episodic tension headache.[21][22] However, the aspirin/paracetamol/caffeine combination 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. Some epidemiological studies have linked paracetamol to cardiovascular, renal, and gastrointestinal diseases, but are largely due to confounding biases and of insignificant relevance with short-term use of paracetamol.[39][40][38][37][41] Paracetamol may slightly increase systolic blood pressure in hypertensive patients at a dose of 4 grams a day.[42][43] Elevated frequency of asthma and developmental and reproductive disorders is observed in the offspring of women with prolonged use of paracetamol during pregnancy, although whether paracetamol is the true cause of this increase is unclear.[42] Some studies suggest that there is evidence for an association between paracetamol during pregnancy and autism spectrum disorder and attention deficit hyperactivity disorder, while making clear further research is required to establish any causal link,[44][45] which has prompted some calls to limit its use in pregnancy to the lowest effective dosage for the shortest possible time.[42][46][47]

The recommended maximum daily dose for an adult is three to four grams.[48][49][27] Higher doses may lead to toxicity, including liver failure.[50] 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.[51][52][53]

Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly 1852 by Charles Frédéric Gerhardt.[54][55][56] It is the most commonly used medication for pain and fever in both the United States and Europe.[57] It is on the World Health Organization's List of Essential Medicines.[58] Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others.[59] In 2021, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[60][61]

Etymology edit

 
Look up paracetamol or acetaminophen in Wiktionary, the free dictionary.

The word "acetaminophen" is a shortened form of N-acetyl aminophenol, and was coined and first marketed by McNeil Laboratories in 1955.[62]

The word "paracetamol" is a shortened form of para-acetyl-amino-phenol,[63] and was coined by Frederick Stearns & Co in 1956.[64]

Medical uses edit

Fever edit

Paracetamol is a drug of choice for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults.[14] The most recent review on paracetamol and management of fever in the general practice (2008) argued that its benefits are unclear.[14] In addition, when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as a sore throat, malaise, sneezing, or cough; however, these data are of poor quality.[65]

For patients in critical care, paracetamol decreased body temperature by only 0.2–0.3 °C more than control interventions; there was no difference in mortality.[16] It did not change the outcome in febrile patients with stroke.[66] 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.[67] 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.[68] 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.[69] It does not prevent febrile seizures and should not be used for that purpose.[69][70] 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[71]), including children younger than 2 years old,[72] with equivalent safety.[18] Exacerbation of asthma occurs with similar frequency for both medications.[73] Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required.[69]

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.[74] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[15]

Musculoskeletal pain edit

The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.[15]

It appears to provide only small and not clinically important benefits in osteoarthritis.[15][27] American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective.[28] The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required.[28] Essentially the same recommendation was issued by EULAR for hand osteoarthritis.[75] Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.[76]

Paracetamol is ineffective for acute low back pain.[15][29] No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.[27][30][29]

Headaches edit

Paracetamol is effective for acute migraine:[21] 39% of people experience pain relief at one hour compared with 20% in the control group.[77] The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".[23] Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.[22] However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: 2 hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.[78] The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".[24]

Dental and other post-surgical pain edit

Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.[79] For the relief of such pain, paracetamol is inferior to ibuprofen.[25] Full therapeutic doses of non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.[80] The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.[25][26][81][82] Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.[26]

A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%.[83]

Other pain edit

Paracetamol fails to relieve procedural pain in newborn babies.[84][85] For perineal pain postpartum paracetamol appears to be less effective than non-steroidal anti-inflammatory drugs (NSAIDs).[86]

The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking.[31][32] There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.[87] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[88]

Patent ductus arteriosus edit

Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen.[89] Its use for extremely low birth weight and gestational age infants however requires further study.[89]

Adverse effects edit

Gastrointestinal adverse effects such as nausea and abdominal pain are common, and their frequency is similar to that of ibuprofen.[37] Increase in risk-taking behavior is possible.[90] According to the US Food and Drug Administration, the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis,[91] Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions.[91][92]

In clinical trials for osteoarthritis, the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.[40] After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to ibuprofen group.[38]

Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.[37] These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol.[38][37][41] Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.[37] Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events.[42] Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%[93] and kidney cancer by 28%.[41] Paracetamol is particularly dangerous to the liver in overdose, but even without overdose those who take this drug may develop acute liver failure requiring liver transplantation more frequently than the users of nonsteroidal anti-inflammatory drugs.[36] Paracetamol slightly but significantly increases blood pressure and heart rate.[37] The majority of observational studies suggests that, used chronically, it may increase the risk of developing hypertension, as confirmed in a prospective randomized confirmed trial.[43] The risk is higher with the higher dose.[42]

The association between paracetamol use and asthma in children has been a matter of controversy.[94] However, the most recent research suggests that there is no association,[95] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen.[73]

Use in pregnancy edit

Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.[42]

Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma,[96][97] but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.[42] Paracetamol, in a small scale meta-analysis was also associated with 20–30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings.[42][98][99] There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.[44][45] In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.[42]

The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time.[42][46][47]

Overdose edit

Main article: Paracetamol poisoning

Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[48][49] and can cause potentially fatal liver damage.[100][101] A single dose should not exceed 1000 mg, and doses should be taken no sooner than four hours apart.[48] While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[102]

Paracetamol toxicity 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.[51][103][52][53] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.[104] According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."[105]

Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.[106] The overdose risk may be heightened by frequent consumption of alcohol.[107]

Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.[108] People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.[109][110]

Treatment is aimed at removing the paracetamol from the body and replenishing glutathione.[110] Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe.[51][111]

NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.[112][113] Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.[110] Kidney failure is also a possible side effect.[107]

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.[114][115] 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.[115]

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.[115] 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.[116] On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.[115]

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.[115]

Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.[115] Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.[117][118][119]

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).[120]

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.[121] 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.[120][121] 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.[120][122] It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase.[120] AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.[120] This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.[120][123]

In 2018, Suemaru et al. found that, in mice, paracetamol exerts anticonvulsant effect by activation of TRPV1 receptors[124] and decrease in neuronal excitability by hyperpolarization of neurons.[125] 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.[124]

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.[126] 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.[127] 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).[128] After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).[128]

 
Important pathways of paracetamol metabolism

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.[129]

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).[129] 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.[129]

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.[127]

Chemistry edit

Synthesis edit

Classical methods edit

 
Classical methods for the production of paracetamol

The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.[130][131][132]

Celanese synthesis edit

An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride to a ketone, then the conversion of the ketone with hydroxylamine to a ketoxime, and finally the acid-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product.[130][133]

 
Celanese method for the preparation of paracetamol

Reactions edit

 
Paracetamol crystals (crystallized from an aqueous solution) under a microscope

4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.[134]

History edit

 
Julius Axelrod (pictured) and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.[135] But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.[136] Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.[55][56]

Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[137][138] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.[136] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[139] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[140]

Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.[140] In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[141] In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.[142][143][144] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[145] This led to a "rediscovery" of paracetamol.[136]

Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine.[138] Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.[138] The following year, 1952, paracetamol returned to the US market as a prescription drug.[146] In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.[147][148] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[147][138]

Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[136] Available in the US without a prescription since 1955[146] (1960, according to another source[149]) paracetamol has become a common household drug.[150] In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.[151]

In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.[152]

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.[153][154][155][156][157] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[154][156]

In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[158]

In September 2013, "Use Only as Directed", an episode of the radio program This American Life[159] highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson"[160] and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[161]

During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated.[162][163][164][165]

Society and culture edit

Naming edit

Paracetamol is the Australian Approved Name[166] and British Approved Name[167] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[167] and Japanese Accepted Name and also the name generally used in Canada,[167] Venezuela, Colombia, and Iran.[167][168] Both paracetamol and acetaminophen are contractions of para-acetylaminophenol, a chemical name for the compound. The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol.[169]

Available forms edit

See also: Paracetamol brand names
 
Tylenol 500 mg capsules
 
Panadol 500 mg tablets
 
For comparison: The pure drug is a colourless crystalline powder.

Paracetamol is available in oral, suppository, and intravenous forms.[170] Intravenous paracetamol is sold under the brand name Ofirmev in the United States.[171]

In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the US, this combination is available only by prescription.[172] As of 1 February 2018, medications containing codeine also became prescription-only in Australia.[173] Paracetamol is also combined with other opioids such as dihydrocodeine,[174] referred to as co-dydramol (British Approved Name (BAN)), oxycodone[175] or hydrocodone.[176] Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate.[177] A combination of paracetamol, codeine, and the doxylamine succinate is also available.[178]

Paracetamol is sometimes combined with phenylephrine hydrochloride.[179] Sometimes a third active ingredient, such as ascorbic acid,[179][180] caffeine,[181][182] chlorpheniramine maleate,[183] or guaifenesin[184][185][186] is added to this combination.

Veterinary use edit

Cats edit

Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobinemia and hemolytic anemia).[187] Treatment of the toxicosis with N-acetylcysteine is recommended.[188]

Dogs edit

Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[189] A paracetamol–codeine product (brand name Pardale-V)[190] licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.[190] It should be administered to dogs only on veterinary advice and with extreme caution.[190]

The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[188][191][192][193] N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[188][189]

Snakes edit

 
Aerial bait cartridges consisting of dead mice with 80 mg paracetamol tablets

Paracetamol is lethal to snakes[194] and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[195][196] Doses of 80 mg are inserted into dead mice that are scattered by helicopter[197] as lethal bait to be consumed by the snakes.

Notes edit

  1. ^ Commonly called "acetaminophen" in the US, Canada, Japan, and South Korea.

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February 16, 2024
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Paracetamol acetaminophen a or para hydroxyacetanilide 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 ParacetamolClinical dataPronunciationParacetamol ˌ p aer e ˈ s iː t e m ɒ l Acetaminophen e ˌ s iː t e ˈ m ɪ n e f ɪ n Trade namesTylenol Panadol others 1 Other namesN acetyl para aminophenol APAP acetaminophen USAN US AHFS Drugs comMonographMedlinePlusa681004License dataUS DailyMed AcetaminophenPregnancycategoryAU A 2 Routes ofadministrationOral by mouth rectal intravenous IV Drug classAnalgesics and antipyreticsATC codeN02BE01 WHO N02BE51 WHO N02BE71 WHO Legal statusLegal statusAU S4 Rx OTC and unscheduled CA OTC Rx only 4 UK General sales list GSL OTC US WARNING 3 OTC Rx onlyPharmacokinetic dataBioavailability63 89 5 73 Protein bindingnegligible to 10 25 in overdose 6 MetabolismPredominantly in the liver 9 MetabolitesAPAP gluc APAP sulfate APAP GSH APAP cys AM404 NAPQI 7 Onset of actionPain relief onset by route oral 37 minutes 8 Intravenous 8 minutes 8 Elimination half life1 9 2 5 hours 6 ExcretionUrine 6 IdentifiersIUPAC name N 4 hydroxyphenyl ethanamideCAS Number103 90 2 YPubChem CID1983PubChem SID46506142IUPHAR BPS5239DrugBankDB00316 YChemSpider1906 YUNII362O9ITL9DKEGGD00217 YC06804ChEBICHEBI 46195 YChEMBLChEMBL112 YPDB ligandTYL PDBe RCSB PDB CompTox Dashboard EPA DTXSID2020006ECHA InfoCard100 002 870Chemical and physical dataFormulaC 8H 9N O 2Molar mass151 165 g mol 13D model JSmol Interactive imageDensity1 263 g cm3Melting point169 C 336 F 10 11 Solubility in water7 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 SMILES CC O Nc1ccc O cc1InChI InChI 1S C8H9NO2 c1 6 10 9 7 2 4 8 11 5 3 7 h2 5 11H 1H3 H 9 10 YKey RZVAJINKPMORJF UHFFFAOYSA N Y verify At a standard dose paracetamol only 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 may relieve pain in acute mild migraine but only slightly in episodic tension headache 21 22 However the aspirin paracetamol caffeine combination 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 Some epidemiological studies have linked paracetamol to cardiovascular renal and gastrointestinal diseases but are largely due to confounding biases and of insignificant relevance with short term use of paracetamol 39 40 38 37 41 Paracetamol may slightly increase systolic blood pressure in hypertensive patients at a dose of 4 grams a day 42 43 Elevated frequency of asthma and developmental and reproductive disorders is observed in the offspring of women with prolonged use of paracetamol during pregnancy although whether paracetamol is the true cause of this increase is unclear 42 Some studies suggest that there is evidence for an association between paracetamol during pregnancy and autism spectrum disorder and attention deficit hyperactivity disorder while making clear further research is required to establish any causal link 44 45 which has prompted some calls to limit its use in pregnancy to the lowest effective dosage for the shortest possible time 42 46 47 The recommended maximum daily dose for an adult is three to four grams 48 49 27 Higher doses may lead to toxicity including liver failure 50 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 51 52 53 Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly 1852 by Charles Frederic Gerhardt 54 55 56 It is the most commonly used medication for pain and fever in both the United States and Europe 57 It is on the World Health Organization s List of Essential Medicines 58 Paracetamol is available as a generic medication with brand names including Tylenol and Panadol among others 59 In 2021 it was the 113th most commonly prescribed medication in the United States with more than 5 million prescriptions 60 61 Contents 1 Etymology 2 Medical uses 2 1 Fever 2 2 Pain 2 2 1 Musculoskeletal pain 2 2 2 Headaches 2 2 3 Dental and other post surgical pain 2 2 4 Other pain 2 3 Patent ductus arteriosus 3 Adverse effects 3 1 Use in pregnancy 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 2 Pharmacokinetics 7 Chemistry 7 1 Synthesis 7 1 1 Classical methods 7 1 2 Celanese synthesis 7 2 Reactions 8 History 9 Society and culture 9 1 Naming 9 2 Available forms 10 Veterinary use 10 1 Cats 10 2 Dogs 10 3 Snakes 11 Notes 12 References 13 External linksEtymology edit nbsp Look up paracetamol or acetaminophen in Wiktionary the free dictionary The word acetaminophen is a shortened form of N acetyl aminophenol and was coined and first marketed by McNeil Laboratories in 1955 62 The word paracetamol is a shortened form of para acetyl amino phenol 63 and was coined by Frederick Stearns amp Co in 1956 64 Medical uses editFever edit Paracetamol is a drug of choice for reducing fever However there has been a lack of research on its antipyretic properties particularly in adults 14 The most recent review on paracetamol and management of fever in the general practice 2008 argued that its benefits are unclear 14 In addition when used for the common cold paracetamol may relieve a stuffed or runny nose but not other cold symptoms such as a sore throat malaise sneezing or cough however these data are of poor quality 65 For patients in critical care paracetamol decreased body temperature by only 0 2 0 3 C more than control interventions there was no difference in mortality 16 It did not change the outcome in febrile patients with stroke 66 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 67 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 68 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 69 It does not prevent febrile seizures and should not be used for that purpose 69 70 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 71 including children younger than 2 years old 72 with equivalent safety 18 Exacerbation of asthma occurs with similar frequency for both medications 73 Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended however doses may be alternated if required 69 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 74 It is recommended in particular for acute mild to moderate pain since the evidence for the treatment of chronic pain is insufficient 15 Musculoskeletal pain edit The benefits of paracetamol in musculoskeletal conditions such as osteoarthritis and backache are uncertain 15 It appears to provide only small and not clinically important benefits in osteoarthritis 15 27 American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small which suggests that for most individuals it is ineffective 28 The guideline conditionally recommends paracetamol for short term and episodic use to those who do not tolerate nonsteroidal anti inflammatory drugs For people taking it regularly monitoring for liver toxicity is required 28 Essentially the same recommendation was issued by EULAR for hand osteoarthritis 75 Similarly the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short term rescue analgesia only 76 Paracetamol is ineffective for acute low back pain 15 29 No randomized clinical trials evaluated its use for chronic or radicular back pain and the evidence in favor of paracetamol is lacking 27 30 29 Headaches edit Paracetamol is effective for acute migraine 21 39 of people experience pain relief at one hour compared with 20 in the control group 77 The aspirin paracetamol caffeine combination also has strong evidence of effectiveness and can be used as a first line treatment for migraine 23 Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently 22 However the aspirin paracetamol caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache 2 hours after administering the medication 29 of those who took the combination were pain free as compared with 21 on paracetamol and 18 on placebo 78 The German Austrian and Swiss headache societies and the German Society of Neurology recommend this combination as a highlighted one for self medication of tension headache with paracetamol caffeine combination being a remedy of first choice and paracetamol a remedy of second choice 24 Dental and other post surgical pain edit Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain 79 For the relief of such pain paracetamol is inferior to ibuprofen 25 Full therapeutic doses of non steroidal anti inflammatory drugs NSAIDs ibuprofen naproxen or diclofenac are clearly more efficacious than the paracetamol codeine combination which is frequently prescribed for dental pain 80 The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising possibly offering better pain control than either paracetamol or the NSAID alone 25 26 81 82 Additionally the paracetamol ibuprofen combination may be superior to paracetamol codeine and ibuprofen codeine combinations 26 A meta analysis of general post surgical pain which included dental and other surgery showed the paracetamol codeine combination to be more effective than paracetamol alone it provided significant pain relief to as much as 53 of the participants while the placebo helped only 7 83 Other pain edit Paracetamol fails to relieve procedural pain in newborn babies 84 85 For perineal pain postpartum paracetamol appears to be less effective than non steroidal anti inflammatory drugs NSAIDs 86 The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking 31 32 There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department 87 The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain 88 Patent ductus arteriosus edit Paracetamol helps ductal closure in patent ductus arteriosus It is as effective for this purpose as ibuprofen or indomethacin but results in less frequent gastrointestinal bleeding than ibuprofen 89 Its use for extremely low birth weight and gestational age infants however requires further study 89 Adverse effects editGastrointestinal adverse effects such as nausea and abdominal pain are common and their frequency is similar to that of ibuprofen 37 Increase in risk taking behavior is possible 90 According to the US Food and Drug Administration the drug may cause rare and possibly fatal skin reactions such as Stevens Johnson syndrome and toxic epidermal necrolysis 91 Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions 91 92 In clinical trials for osteoarthritis the number of participants reporting adverse effects was similar for those on paracetamol and on placebo However the abnormal liver function tests meaning there was some inflammation or damage to the liver were almost four times more likely in those on paracetamol although the clinical importance of this effect is uncertain 40 After 13 weeks of paracetamol therapy for knee pain a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20 of participants this rate being similar to ibuprofen group 38 Due to the absence of controlled studies most of the information about the long term safety of paracetamol comes from observational studies 37 These indicate a consistent pattern of increased mortality as well as cardiovascular stroke myocardial infarction gastrointestinal ulcers bleeding and renal adverse effects with increased dose of paracetamol 38 37 41 Use of paracetamol is associated with 1 9 times higher risk of peptic ulcer 37 Those who take it regularly at a higher dose more than 2 3 g daily are at much higher risk 3 6 3 7 times of gastrointestinal bleeding and other bleeding events 42 Meta analyses suggest that paracetamol may increase the risk of kidney impairment by 23 93 and kidney cancer by 28 41 Paracetamol is particularly dangerous to the liver in overdose but even without overdose those who take this drug may develop acute liver failure requiring liver transplantation more frequently than the users of nonsteroidal anti inflammatory drugs 36 Paracetamol slightly but significantly increases blood pressure and heart rate 37 The majority of observational studies suggests that used chronically it may increase the risk of developing hypertension as confirmed in a prospective randomized confirmed trial 43 The risk is higher with the higher dose 42 The association between paracetamol use and asthma in children has been a matter of controversy 94 However the most recent research suggests that there is no association 95 and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen 73 Use in pregnancy edit Paracetamol safety in pregnancy has been under increased scrutiny There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects However indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy 42 Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma 96 97 but so are the maternal infections for which paracetamol may be used and separating these influences is difficult 42 Paracetamol in a small scale meta analysis was also associated with 20 30 increase in autism spectrum disorder attention deficit hyperactivity disorder hyperactivity symptoms and conduct disorder with the association being lower in a meta analysis where a larger demographic was used but it is unclear whether this is a causal relationship and there was potential bias in the findings 42 98 99 There is also an argument that the large number consistency and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders 44 45 In animal experiments paracetamol disrupts fetal testosterone production and several epidemiological studies linked cryptorchidism with mother s paracetamol use for more than two weeks in the second trimester On the other hand several studies did not find any association 42 The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary at the lowest effective dosage and for the shortest time 42 46 47 Overdose editMain article Paracetamol poisoning Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults three or four grams 48 49 and can cause potentially fatal liver damage 100 101 A single dose should not exceed 1000 mg and doses should be taken no sooner than four hours apart 48 While a majority of adult overdoses are linked to suicide attempts many cases are accidental often due to the use of more than one paracetamol containing product over an extended period 102 Paracetamol toxicity 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 51 103 52 53 Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance 104 According to the FDA in the United States 56 000 emergency room visits 26 000 hospitalizations and 458 deaths per year were related to acetaminophen associated overdoses during the 1990s Within these estimates unintentional acetaminophen overdose accounted for nearly 25 of the emergency department visits 10 of the hospitalizations and 25 of the deaths 105 Overdoses are frequently related to high dose recreational use of prescription opioids as these opioids are most often combined with paracetamol 106 The overdose risk may be heightened by frequent consumption of alcohol 107 Untreated paracetamol overdose results in a lengthy painful illness Signs and symptoms of paracetamol toxicity may initially be absent or non specific symptoms The first symptoms of overdose usually begin several hours after ingestion with nausea vomiting sweating and pain as acute liver failure starts 108 People who take overdoses of paracetamol do not fall asleep or lose consciousness although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug 109 110 Treatment is aimed at removing the paracetamol from the body and replenishing glutathione 110 Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose While the antidote acetylcysteine also called N acetylcysteine or NAC acts as a precursor for glutathione helping the body regenerate enough to prevent or at least decrease the possible damage to the liver a liver transplant is often required if damage to the liver becomes severe 51 111 NAC was usually given following a treatment nomogram one for people with risk factors and one for those without but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice 112 113 Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it 110 Kidney failure is also a possible side effect 107 Interactions editProkinetic 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 114 115 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 115 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 115 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 116 On the other hand the anti tuberculosis drug isoniazid cuts the formation of NAPQI by 70 115 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 115 Paracetamol raises plasma concentrations of ethinylestradiol by 22 by inhibiting its sulfation 115 Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week 117 118 119 Pharmacology editPharmacodynamics edit Paracetamol appears to exert its effects through two mechanisms the inhibition of cyclooxygenase and actions of its metabolite N arachidonoylphenolamine AM404 120 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 121 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 120 121 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 120 122 It is formed in the brain from another paracetamol metabolite 4 aminophenol by action of fatty acid amide hydrolase 120 AM404 is a weak agonist of cannabinoid receptors CB1 and CB2 an inhibitor of endocannabinoid transporter and a potent activator of TRPV1 receptor 120 This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol 120 123 In 2018 Suemaru et al found that in mice paracetamol exerts anticonvulsant effect by activation of TRPV1 receptors 124 and decrease in neuronal excitability by hyperpolarization of neurons 125 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 124 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 126 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 127 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 mg mL 200 mmol L 128 After 4 hours the concentration is usually less than 10 mg mL 66 mmol L 128 nbsp Important pathways of paracetamol metabolismParacetamol 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 129 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 129 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 129 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 127 Chemistry editSynthesis edit Classical methods edit nbsp Classical methods for the production of paracetamolThe classical methods for the production of paracetamol involve the acetylation of 4 aminophenol with acetic anhydride as the last step They differ in how 4 aminophenol is prepared In one method nitration of phenol with nitric acid affords 4 nitrophenol which is reduced to 4 aminophenol by hydrogenation over Raney nickel In another method nitrobenzene is reduced electrolytically giving 4 aminophenol directly Additionally 4 nitrophenol can be selectively reduced by Tin II Chloride in absolute ethanol or ethyl acetate to produce a 91 yield of 4 aminophenol 130 131 132 Celanese synthesis edit An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride to a ketone then the conversion of the ketone with hydroxylamine to a ketoxime and finally the acid catalyzed Beckmann rearrangement of the cetoxime to the para acetylaminophenol product 130 133 nbsp Celanese method for the preparation of paracetamolReactions edit nbsp Paracetamol crystals crystallized from an aqueous solution under a microscope4 Aminophenol may be obtained by the amide hydrolysis of paracetamol This reaction is also used to determine paracetamol in urine samples After hydrolysis with hydrochloric acid 4 aminophenol reacts in ammonia solution with a phenol derivate e g salicylic acid to form an indophenol dye under oxidization by air 134 History edit nbsp Julius Axelrod pictured and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol which is a better tolerated analgesic Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties and was quickly introduced into medical practice under the name of Antifebrin by Cahn amp Hepp in 1886 135 But its unacceptable toxic effects the most alarming being cyanosis due to methemoglobinemia an increase of hemoglobin in its ferric Fe3 state called methemoglobin which cannot bind oxygen and thus decreases overall carriage of oxygen to tissue prompted the search for less toxic aniline derivatives 136 Some reports state that Cahn amp Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852 55 56 Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p nitrophenol with tin in glacial acetic acid in 1877 137 138 but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans 136 In 1893 von Mering published a paper reporting on the clinical results of paracetamol with phenacetin another aniline derivative 139 Von Mering claimed that unlike phenacetin paracetamol had a slight tendency to produce methemoglobinemia Paracetamol was then quickly discarded in favor of phenacetin The sales of phenacetin established Bayer as a leading pharmaceutical company 140 Von Mering s claims remained essentially unchallenged for half a century until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin 140 In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia 141 In 1948 Bernard Brodie Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans and established that it was just as efficacious an analgesic as its precursor 142 143 144 They also suggested that methemoglobinemia is produced in humans mainly by another metabolite phenylhydroxylamine A follow up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol 145 This led to a rediscovery of paracetamol 136 Paracetamol was first marketed in the United States in 1950 under the name Triagesic a combination of paracetamol aspirin and caffeine 138 Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace and it took several years until it became clear that the disease was unconnected 138 The following year 1952 paracetamol returned to the US market as a prescription drug 146 In the United Kingdom marketing of paracetamol began in 1956 by Sterling Winthrop Co as Panadol available only by prescription and promoted as preferable to aspirin since it was safe for children and people with ulcers 147 148 In 1963 paracetamol was added to the British Pharmacopoeia and has gained popularity since then as an analgesic agent with few side effects and little interaction with other pharmaceutical agents 147 138 Concerns about paracetamol s safety delayed its widespread acceptance until the 1970s but in the 1980s paracetamol sales exceeded those of aspirin in many countries including the United Kingdom This was accompanied by the commercial demise of phenacetin blamed as the cause of analgesic nephropathy and hematological toxicity 136 Available in the US without a prescription since 1955 146 1960 according to another source 149 paracetamol has become a common household drug 150 In 1988 Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994 151 In June 2009 an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects The maximum single adult dosage would be decreased from 1000 mg to 650 mg while combinations of paracetamol and other products would be prohibited Committee members were particularly concerned by the fact that the then present maximum dosages of paracetamol had been shown to produce alterations in liver function 152 In January 2011 the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage 153 154 155 156 157 Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit 154 156 In November 2011 the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children 158 In September 2013 Use Only as Directed an episode of the radio program This American Life 159 highlighted deaths from paracetamol overdose This report was followed by two reports by ProPublica alleging that the FDA has long been aware of studies showing the risks of acetaminophen So has the maker of Tylenol McNeil Consumer Healthcare a division of Johnson amp Johnson 160 and McNeil the maker of Tylenol has repeatedly opposed safety warnings dosage restrictions and other measures meant to safeguard users of the drug 161 During the COVID 19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID 19 but this was found to be unsubstantiated 162 163 164 165 Society and culture editNaming edit Paracetamol is the Australian Approved Name 166 and British Approved Name 167 as well as the international nonproprietary name used by the WHO and in many other countries acetaminophen is the United States Adopted Name 167 and Japanese Accepted Name and also the name generally used in Canada 167 Venezuela Colombia and Iran 167 168 Both paracetamol and acetaminophen are contractions of para acetylaminophenol a chemical name for the compound The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name N acetyl para aminophenol 169 Available forms edit See also Paracetamol brand names nbsp Tylenol 500 mg capsules nbsp Panadol 500 mg tablets nbsp For comparison The pure drug is a colourless crystalline powder Paracetamol is available in oral suppository and intravenous forms 170 Intravenous paracetamol is sold under the brand name Ofirmev in the United States 171 In some formulations paracetamol is combined with the opiate codeine sometimes referred to as co codamol BAN and Panadeine in Australia In the US this combination is available only by prescription 172 As of 1 February 2018 medications containing codeine also became prescription only in Australia 173 Paracetamol is also combined with other opioids such as dihydrocodeine 174 referred to as co dydramol British Approved Name BAN oxycodone 175 or hydrocodone 176 Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate 177 A combination of paracetamol codeine and the doxylamine succinate is also available 178 Paracetamol is sometimes combined with phenylephrine hydrochloride 179 Sometimes a third active ingredient such as ascorbic acid 179 180 caffeine 181 182 chlorpheniramine maleate 183 or guaifenesin 184 185 186 is added to this combination Veterinary use editCats edit Paracetamol is extremely toxic to cats which lack the necessary UGT1A6 enzyme to detoxify it Initial symptoms include vomiting salivation and discoloration of the tongue and gums Unlike an overdose in humans liver damage is rarely the cause of death instead methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood causing asphyxiation methemoglobinemia and hemolytic anemia 187 Treatment of the toxicosis with N acetylcysteine is recommended 188 Dogs edit Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs 189 A paracetamol codeine product brand name Pardale V 190 licensed for use in dogs is available for purchase under supervision of a vet pharmacist or other qualified person 190 It should be administered to dogs only on veterinary advice and with extreme caution 190 The main effect of toxicity in dogs is liver damage and GI ulceration has been reported 188 191 192 193 N acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion 188 189 Snakes edit nbsp Aerial bait cartridges consisting of dead mice with 80 mg paracetamol tabletsParacetamol is lethal to snakes 194 and has been suggested as a chemical control program for the invasive brown tree snake Boiga irregularis in Guam 195 196 Doses of 80 mg are inserted into dead mice that are scattered by helicopter 197 as lethal bait to be consumed by the snakes Notes edit Commonly called acetaminophen in the US Canada Japan and South Korea References edit International Drug Names Acetaminophen Use During Pregnancy Drugs com 14 June 2019 Archived from the original on 9 March 2020 Retrieved 25 February 2020 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 October 2023 Regulatory Decision Summary Acetaminophen Injection Health Canada 23 October 2014 Archived from the original on 7 June 2022 Retrieved 7 June 2022 Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine 2015 Schug SA Palmer GM Scott DA Halliwell R Trinca J eds Acute Pain Management Scientific Evidence 4th ed Melbourne Australian and New Zealand College of Anaesthetists ANZCA Faculty of Pain Medicine FPM ISBN 978 0 9873236 7 5 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