Paracetamol
others[1] | |
Other names | N-acetyl-para-aminophenol (APAP), acetaminophen (USAN US) |
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AHFS/Drugs.com | Monograph |
MedlinePlus | a681004 |
License data | |
Pregnancy category |
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intravenous (IV) | |
Drug class | Analgesics and antipyretics |
ATC code | |
Legal status | |
Legal status | |
Elimination half-life | 1.9–2.5 hours[6] |
Excretion | Urine[6] |
Identifiers | |
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JSmol) | |
Density | 1.263 g/cm3 |
Melting point | 169 °C (336 °F) [10][11] |
Solubility in water | |
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Paracetamol (acetaminophen
At a standard dose, paracetamol slightly decreases body temperature;
In the short term, paracetamol is safe and effective when used as directed.
Paracetamol was first made in 1878 by
Medical uses
Fever
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.[53]
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.[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.
Pain
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]
Musculoskeletal pain
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
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
Paracetamol is effective for acute migraine:[21] 39% of people experience pain relief at one hour compared with 20% in the control group.[65] 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.[66] 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
Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.
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%.[71]
Other pain
Paracetamol fails to relieve procedural pain in
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.[75] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[76]
Patent ductus arteriosus
Paracetamol helps ductal closure in
Adverse effects
Gastrointestinal adverse effects such as nausea and
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.[81] 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][82] 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.[83] Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%[84] and kidney cancer by 28%.[82] 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.[85] The risk is higher with the higher dose.[83]
The association between paracetamol use and asthma in children has been a matter of controversy.[86] However, the most recent research suggests that there is no association,[87] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen.[61]
Use in pregnancy
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
Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood
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.[83][94][95]
Overdose
Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[39][40] and can cause potentially fatal liver damage.[96][97] A single dose should not exceed 1000 mg, and doses should be taken no sooner than four hours apart.[39] 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.[98]
Overdoses are frequently related to high-dose
Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or
Treatment is aimed at removing the paracetamol from the body and replenishing
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.[108][109] Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.[106] Kidney failure is also a possible side effect.[103]
Interactions
There have been suspicions that
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
Pharmacodynamics
Paracetamol appears to exert its effects through two mechanisms: the inhibition of
Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical
The second mechanism centers on the paracetamol metabolite
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
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
A minor metabolic pathway (5–15%) of
Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form
Chemistry
Synthesis
Classical methods
The classical methods for the production of paracetamol involve the
Celanese synthesis
An alternative industrial synthesis developed at
Reactions
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.[130]
History
Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[133][134] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.[132] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[135] 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.[136]
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.
Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol,
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
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.[148]
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.[149][150][151][152][153] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[150][152]
In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[154]
In September 2013, "Use Only as Directed", an episode of the radio program This American Life[155] 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"[156] and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[157]
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.[158][159][160][161]
Society and culture
Naming
Paracetamol is the Australian Approved Name[162] and British Approved Name[163] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[163] and Japanese Accepted Name and also the name generally used in Canada,[163] Venezuela, Colombia, and Iran.[163][164] 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.[165] The word "paracetamol" is a shortened form of para-acetyl-amino-phenol,[166] and was coined by Frederick Stearns & Co in 1956.[167] The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol.[168]
Available forms
Paracetamol is available in oral, suppository, and
In some formulations, paracetamol is combined with the
Paracetamol is sometimes combined with
Veterinary use
Cats
Paracetamol is extremely toxic to cats, which lack the necessary
Dogs
Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[188] A paracetamol–codeine product (brand name Pardale-V)[189] licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.[189] It should be administered to dogs only on veterinary advice and with extreme caution.[189]
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[187][190][191][192] N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[187][188]
Snakes
Paracetamol is lethal to snakes[193] and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[194][195] Doses of 80 mg are inserted into dead mice that are scattered by helicopter[196] as lethal bait to be consumed by the snakes.
Notes
- ^ Commonly called "acetaminophen" in the US, Canada, Japan, and South Korea.
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