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Key:RZVAJINKPMORJF-UHFFFAOYSA-N Y Paracetamol, also known as acetaminophen and APAP, is a medication used to treat. It is typically used for mild to moderate pain relief. There is mixed evidence for its use to relieve fever in children. It is often sold in combination with other medications, such as in many. Paracetamol is also used for severe pain, such as and pain after surgery, in combination with. It is typically used either by mouth or, but is also available. Effects last between 2 to 4 hours.
Paracetamol is generally safe at recommended doses. The recommended maximum daily dose for an adult is 3 or 4 grams. Higher doses may lead to toxicity, including. Serious skin rashes may rarely occur. It appears to be safe during and when. In those with liver disease, it may still be used, but in lower doses. It is classified as a mild.
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It does not have significant activity. How it works is not entirely clear. Paracetamol was first made in 1877. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the, which lists the most effective and safe medicines needed in a. Paracetamol is available as a with trade names including and, among others.
The wholesale price in the is less than 0.01 per dose. In the United States, it costs about US$0.04 per dose. In 2016, it was the 17th most prescribed medication in the United States, with more than 29 million prescriptions. Contents.
Medical uses Fever Paracetamol is used for reducing in people of all ages. The recommends that paracetamol be used to treat fever in children only if their temperature is higher than 38.5 °C (101.3 °F). The efficacy of paracetamol by itself in children with fevers has been questioned and a meta-analysis showed that it is less effective than. Paracetamol does not have significant effects.
Pain Paracetamol is used for the relief of mild to moderate pain. The use of the intravenous form for short-term pain in people in the emergency department is supported by limited evidence.
Osteoarthritis The recommends paracetamol as one of several treatment options for people with arthritis pain of the hip, hand, or knee that does not improve with exercise and weight loss. A 2015 review, however, found it provided only a small benefit in. Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the (NSAIDs), and, but ibuprofen and paracetamol have similar effects in the treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no effect on the underlying inflammation, redness, and swelling of the joint. It has properties comparable to those of, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin due to concerns about bleeding with aspirin.
Lower back Based on a systematic review, paracetamol is recommended by the as a first-line treatment for lower back pain. In contrast, the found good evidence for NSAIDs but only fair evidence for paracetamol, while other systematic reviews have concluded that evidence for its efficacy is lacking entirely. Headaches A joint statement of the German, Austrian, and Swiss headache societies and the German Society of Neurology recommends the use of paracetamol in combination with caffeine as one of several first-line therapies for treatment of tension or headache. In the treatment of acute migraine, it is superior to placebo, with 39% of people experiencing pain relief at 1 hour compared with 20% in the control group. Postoperative Paracetamol combined with NSAIDs may be more effective for treating postoperative pain than either paracetamol or NSAIDs alone.
Teeth NSAIDs such as ibuprofen, and are more effective than paracetamol for controlling dental pain or pain arising from dental procedures; combinations of NSAIDs and paracetamol are more effective than either alone. Paracetamol is particularly useful when are contraindicated due to hypersensitivity or history of gastrointestinal ulceration or bleeding. It can also be used in combination with NSAIDs when these are ineffective in controlling dental pain alone.
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The of preoperative analgesics for additional pain relief in children and adolescents shows no evidence of benefit in taking paracetamol before dental treatment to help reduce pain after treatment for procedures under local anaesthetic, but the quality of evidence is low. Other The efficacy of paracetamol when used in combination with weak opioids (such as ) improved for about 50% of people, but with increases in the number experiencing side effects. Combination drugs of paracetamol and strong opioids such as morphine improve analgesic effect.
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The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of common pain conditions, including dental pain, post partum pain, and headache. Patent ductus arteriosus Paracetamol is used to treat, a condition that affects newborns when a blood vessel used in developing the lungs fails to close as it normally does, but evidence for the safety and efficacy of paracetamol for this purpose is lacking. NSAIDs, particularly and ibuprofen, have also been used, but the evidence for them is also not strong. The condition appears to be caused in part by overactive (PGE 2), signalling primarily through its, but possibly also through its. Adverse effects Healthy adults taking regular doses up to 4,000 mg a day shows little evidence of toxicity (although some researchers disagree ).
They are more likely to have abnormal liver function tests, but the importance of this is uncertain. Liver damage Acute of paracetamol can cause potentially fatal. In 2011, the launched a public-education program to help consumers avoid overdose, warning: 'Acetaminophen can cause serious liver damage if more than directed is used.'
In a 2011 Safety Warning, the FDA immediately required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury and required that such combinations contain no more than 325 mg of acetaminophen. Overdoses are frequently related to high-dose of prescription, as these opioids are most often combined with acetaminophen. The overdose risk may be heightened by frequent consumption of alcohol. Is the foremost cause of in the, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. 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.'
Paracetamol is metabolised by the liver and is; side effects are multiplied when combined with alcoholic drinks, and are very likely in or people with liver damage. Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such as when high doses are taken chronically. Is seen in rare cases, most commonly in overdose. Skin reactions On August 2, 2013, the United States Food and Drug Administration issued a new warning about paracetamol.
It stated that the drug could cause rare and possibly fatal skin reactions such as. Prescription-strength products will be required to carry a warning label about skin reactions, and the FDA has urged manufacturers to do the same with over-the-counter products. Asthma An association exists between paracetamol use and, but whether this association is causal is still debated as of 2017. Certain evidence suggests that this association likely reflects rather than being truly causal. A 2014 review found that among children, the association disappeared when respiratory infections were taken into account. As of 2014, the and the continue to recommend paracetamol for pain and discomfort in children, but some experts have recommended that paracetamol use by children with asthma or at risk for asthma should be avoided. Other factors In contrast to aspirin, paracetamol does not prevent blood from clotting (it is not an ), thus may be used in people who have concerns with blood.
Additionally it does not cause gastric irritation. However, paracetamol does not help reduce inflammation, while aspirin does. Compared with —whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects. Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with a risk of in children with viral illnesses. If taken recreationally with opioids, weak evidence suggests that it may cause hearing loss. Overdose. Main article: In general the recommended maximum daily dose of paracetamol for healthy adults is 3 or 4 grams.
Higher doses may lead to toxicity. Untreated paracetamol overdose results in a lengthy, painful illness.
Signs and symptoms of paracetamol toxicity may initially be absent. The first symptoms of overdose usually begin several hours after ingestion, with, sweating, and as starts. 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. The process of dying from an overdose takes from 3–5 days to 4–6 weeks. Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in both the United States and the United Kingdom. Paracetamol overdose results in more calls to in the US than overdose of any other pharmacological substance.
Toxicity of paracetamol is believed to be due to its. Untreated overdose can lead to and death within days. Treatment is aimed at removing the paracetamol from the body and replenishing. Can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, (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 is often required if damage to the liver becomes severe.
NAC was usually given following a treatment (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. NAC also helps in neutralizing the imidoquinone metabolite of paracetamol. Is also a possible side effect. Until 2004, tablets were available in the UK (brand-name Paradote) that combined paracetamol with an antidote to protect the liver in case of an overdose. One theoretical, but rarely if ever used, option in the United States is to request a to make a similar drug mix for people who are at risk.
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 dosage at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and opioid analgesics 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 hepatic function. 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. Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit. In November 2011, the revised UK dosing of liquid paracetamol for children. Pregnancy Experimental studies in animals and cohort studies in humans indicate no detectable increase in congenital malformations associated with paracetamol use during.
Additionally, paracetamol does not affect the closure of the fetal as NSAIDs can. Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood. It is also associated with an increase in but it is unclear whether the relationship is causal. A 2015 review states that paracetamol remains a first-line recommended medication for pain and fever during pregnancy, despite these concerns. Cancer Some studies have found an association between paracetamol and a slight increase in, but no effect on risk.
Interactions. – Endogenous The mechanism of action of paracetamol is not completely understood. Unlike NSAIDs such as aspirin, paracetamol does not appear to inhibit the function of any (COX) enzyme outside the, and this appears to be the reason why it is not useful as an. It does appear to selectively inhibit activities in the brain, which may contribute to its ability to treat fever and pain. This activity does not appear to be direct inhibition by blocking an active site, but rather by COX, which must be oxidized in order to function. Paracetamol apparently might modulate the in the brain through its metabolite, which appears to inhibit the reuptake of the endogenous cannabinoid/vanilloid by neurons, making it more available to reduce pain. AM404 also appears to be able to directly activate the (older name: vanilloid receptor), which also inhibits pain signals in the brain.
Pharmacokinetics. Main pathways of paracetamol metabolism (click to enlarge): Pathways shown in blue and purple lead to nontoxic metabolites; the pathway in red leads to toxic. After being taken by mouth, it is rapidly absorbed by the gastrointestinal (GI) tract (although absorption through the stomach is negligible); its is roughly 50 L. The concentration in serum after a typical dose of paracetamol usually peaks below 30 µg/ml (200 µmol/L). After 4 hours, the concentration is usually less than 10 µg/ml (66 µmol/L). Paracetamol is primarily in the liver, into toxic and nontoxic products.
Three are notable:. (45-55%), by and;. Sulfation (sulfate conjugation) (20–30%) by;. N-hydroxylation and dehydration, then glutathione conjugation, (less than 15%).
The hepatic enzyme system metabolises paracetamol (mainly ), forming a minor yet significant alkylating metabolite known as ( N-acetyl- p-benzoquinone imine) (also known as N-acetylimidoquinone). NAPQI is then irreversibly conjugated with the of. All three pathways yield final products that are inactive, nontoxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the of paracetamol; this constitutes an example of.
Production of NAPQI is due primarily to two of cytochrome P450:. At usual doses, NAPQI is quickly detoxified by conjugation with glutathione. Chemistry Chemical properties. Paracetamol electrostatic potential map Paracetamol consists of a ring core, by one group and the atom of an group in the para (1,4). The amide group is (ethanamide). It is an extensively, as the on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the on the carbon, and the lone pair on the carbonyl oxygen are all conjugated.
The presence of two activating groups also make the benzene ring highly reactive toward aromatic substitution. As the substituents are ortho, para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the.
Paracetamol is part of the class of drugs known as ' analgesics'; it is the only such drug still in use today. It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor). This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity. Synthesis Original (Boots) method The original method for production involves the of with gives a mixture of two isomers, from which the wanted (bp 279 °C) can easily be separated. In this reaction, phenol's oxygen is strongly activating, thus the reaction requires only mild conditions as compared to nitration of benzene itself. The is then reduced to an amine, giving. Finally, the amine is acetylated with.
Industrially direct hydrogenation is used, but in the laboratory scale sodium borohydride serves. Green synthesis An alternative industrial synthesis developed by – involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a with, followed by the acid-catalyzed to give the amide.
Direct synthesis More recently (2014) a 'one-pot' synthesis from has been described before the Royal Society of Chemistry. The process may be summarized as follows: Hydroquinone, and were mixed in an argon atmosphere and heated slowly to 230 °C.
The mixture was stirred at this temperature for 15 hours. After cooling the acetic acid was evaporated and the precipitate was filtered, washed with water and dried to give paracetamol as a white solid. The authors go on to claim an 88% yield and 99% purity.
Reactions may be obtained by the amide of paracetamol. 4-Aminophenol prepared this way, and related to the commercially available, has been used as a developer in photography by hobbyists. 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 dye under oxidization by air. (pictured) and demonstrated that acetanilide and phenacetin are both metabolised to paracetamol, which is a better tolerated analgesic. Was the first derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of by Cahn & Hepp in 1886. But its unacceptable toxic effects – the most alarming being due to – prompted the search for less toxic aniline derivatives. Harmon Northrop Morse had already synthesized paracetamol at via the reduction of with in glacial in 1877, but it was not until 1887 that clinical pharmacologist tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with, another aniline derivative.
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 as a leading pharmaceutical company. Overshadowed in part by, introduced into medicine by in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter 'headache mixtures', usually containing phenacetin, an derivative of aspirin, caffeine, and sometimes a. Paracetamol is the active metabolite of and, both once popular as analgesics and antipyretics in their own right. However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered at therapeutic doses.
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 paracetamol. In 1947 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.
In three papers published in the September 1948 issue of the, and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established that it was just as efficacious an analgesic as its precursor. They also suggested that methemoglobinemia is produced in humans mainly by another metabolite,. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolised to paracetamol. This led to a 'rediscovery' of paracetamol. It has been suggested that contamination of paracetamol with, the substance von Mering synthesised it from, may be the cause for his spurious findings. Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol,. Reports in 1951 of three users stricken with the blood disease led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.
Paracetamol was marketed in 1953 by as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. In 1955, paracetamol was marketed as Children's Elixir. In 1956, 500 tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Inc. In 1963, paracetamol was added to the, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents. 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 and hematological toxicity.
In 1988 was acquired by which sold the over the counter drug rights to in 1994. Available since 1959, it has since become a common household drug. On paracetamol have long expired, and generic versions of the drug are widely available.
Society and culture Naming Acetaminophen is the name generally used in the United States , Japan , Canada Venezuela, Colombia, and Iran; paracetamol is used in international venues (, ). In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as APAP, for acetyl- para- amino phenol. Both acetaminophen and paracetamol come from a chemical name for the compound: para- acetyl aminophenol and para- acetyl aminophen ol.
Cost The wholesale price in the is less than $0.01 per dose. In the United States it costs about US$0.04 per dose. In the UK, paracetamol is one of the most prescribed drugs by the NHS. In the UK, Paracetamol costs 19p in the supermarket, while the NHS spends 80 m pounds yearly.
In Europe, prices differ from country to country; low-cost prices for 10 doses could reach €0.54 in Portugal, €0.91 in France and €1.97 in Germany. Available forms. For comparison: The pure drug is a white crystalline powder.
Paracetamol is available in a, liquid suspension, and forms. In some formulations, paracetamol is combined with the, sometimes referred to as and Panadeine in Australia. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over the counter in Canada, and in other countries other strengths may be available over the counter. Paracetamol is also combined with other opioids such as, referred to as ,. Another very commonly used analgesic combination includes paracetamol in combination with. A combination of paracetamol, codeine, and the calmative is also available.
The efficacy of paracetamol/codeine combinations has been questioned by recent research. Paracetamol is commonly used in multi-ingredient preparations for headache, typically including and paracetamol with or without, and sometimes containing codeine.
Paracetamol is sometimes combined with. Sometimes a third active ingredient, such as, or is added to this combination. When marketed in combination with, it is frequently given the label 'PM' and is meant as a sleep aid. Diphenhydramine hydrochloride is known to have hypnotic effects and is non-habit forming. Unfortunately it has been implicated in the occasional development of.
Controversy In September 2013, an episode of titled 'Use Only as Directed' highlighted deaths from paracetamol overdose. This report was followed by two reports by 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' and 'McNeil, the maker of Tylenol. Has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug.'
A report prepared by an internal FDA working group describes a history of FDA initiatives designed to educate consumers about the risk of paracetamol overdose and notes that one challenge to the Agency has been 'identifying the appropriate message about the relative safety of acetaminophen, especially compared to other OTC pain relievers (e.g., aspirin and other NSAIDs)'. The report notes that 'Chronic use of NSAIDs is also associated with significant morbidity and mortality. NSAID gastrointestinal risk is substantial, with deaths and hospitalization estimated in one publication as 3200 and 32,000 per year respectively. Possible cardiovascular toxicity with chronic NSAID use has been a major discussion recently', finally noting that 'The goal of the educational efforts is not to decrease appropriate acetaminophen use or encourage substitution of NSAID use, but rather to educate consumers so that they can avoid unnecessary health risks.' Veterinary use Cats Paracetamol is extremely toxic to cats, which lack the necessary enzyme to break it down safely.
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, formation and the production of in red blood cells inhibit oxygen transport by the blood, causing ( and ).
Treatment with, or both is sometimes effective after the ingestion of small doses of paracetamol. Dogs Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs. A paracetamol-codeine product (trade name Pardale-V) licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person. It should be administered to dogs only on veterinary advice and with extreme caution.
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion. Snakes Paracetamol is lethal to snakes, and has been suggested as a chemical control program for the invasive ( Boiga irregularis) in.
Doses of 80 mg are inserted into dead mice scattered by helicopter. References. The American Society of Health-System Pharmacists. From the original on 5 June 2016.
Retrieved 16 September 2016. From the original on 6 January 2016.
Retrieved 11 January 2016. TGA eBusiness Services. Alphapharm Pty Limited.
29 April 2013. Retrieved 10 May 2014.
Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2010). Macintyre, PE; Schug, SA; Scott, DA; Visser, EJ; Walker, SM, eds. (PDF) (3rd ed.). Melbourne, Australia: National Health and Medical Research Council.
Archived from (PDF) on 2012-10-21. Medscape Reference. From the original on 14 April 2014. Retrieved 10 May 2014. From the original on 4 March 2016. Retrieved 13 January 2016. ^ Pickering G, Macian N, Libert F, Cardot JM, Coissard S, Perovitch P, Maury M, Dubray C (September 2014).
8: 1621–1627. BAPAP has a faster time of antinociception onset (15 minutes, P.
Salicylic acids:.; Acetic acids:.; Propionic acids:.; Anthranilic acids (fenamic acids):.; Pyrazolones:.; Enolic acids (oxicams):.; 4-Aminoquinolines:.; Quinazolines:.; Aminonicotinic acids:.; Sulfonanilides:.; Aminophenols (anilines):.; Selective COX-2 inhibitors (coxibs):.; Others/unsorted:.