ACETAMINOPHEN

Acetaminophen

Systematic (IUPAC) name

N-(4-hydroxyphenyl)ethanamide N-(4-hydroxyphenyl)acetamide

Clinical data Trade names Actamin Maximum Strength (USA), Altenol (USA), Alvedon (Sweden), Aminofen (USA), Anacin Aspirin Free (USA), Apra (USA), Feverall (USA), Genapap (USA), Pamol (Sweden), Panodil (Sweden), Perfalgan (Sweden), Reliv (Sweden), Tylenol (USA) AHFS/Drugs.com monograph MedlinePlus Licence data Pregnancy cat. Legal status Routes a681004 US FDA:link A(AU) B(US) safe Unscheduled (AU) GSL (UK) OTC (US) Oral, rectal, intravenous

Pharmacokinetic data Bioavailability Metabolism Half-life Excretion ~100% 90 to 95% Hepatic 14 h Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 103-90-2 N02BE01 CID 1983 DB00316 1906 362O9ITL9D D00217 CHEBI:116450 CHEMBL112 Chemical data Formula Mol. mass SMILES InChI[show] C8H9NO2 151.17 g/mol eMolecules & PubChem

Physical data

Density Melt. point Solubility in water

1.263 g/cm 169 C (336 F) [2][3] 12.78[1] mg/mL (20 C)

GENERIC NAME: Acetaminophen BRAND NAME: Tylenol and others Other names
APAP N-acetyl-para-aminophenol Paracetamol

It is the active metabolite of phenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered to be carcinogenic at therapeutic doses. The words acetaminophen (used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran) and paracetamol (used elsewhere) both come from chemical names for the compound: para-acetylaminophenol and paraacetylaminophenol. In some contexts, it is simply abbreviated as APAP, for acetyl-paraaminophenol.

Drug Class and Mechanism

Acetaminophen belongs to a class of drugs called analgesics (pain relievers) and antipyretics (fever reducers). The exact mechanism of action of acetaminophen is not known. Acetaminophen relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it. It reduces fever through its action on the heat-regulating center of the brain. Specifically, it tells the center to lower the body's temperature when the temperature is elevated. The FDA approved acetaminophen in 1951. Preparations Liquid suspension, chewable tablets, coated caplets, gelcaps, geltabs, and suppositories. Common dosages are 325, 500 and 650 mg.

What storage conditions are needed for this medicine?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature 15-30C (59-86F) and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

Prescribed for:
Acetaminophen is used for the relief of fever as well as aches and pains associated with many conditions. Acetaminophen relieves pain in mild arthritis but has no effect on the underlying inflammation, redness, and swelling of the joint. If the pain is not due to inflammation,

acetaminophen is as effective as aspirin. It is as effective as the non-steroidal antiinflammatory drug ibuprofen (Motrin) in relieving the pain of osteoarthritis of the knee. Unless directed by physician, acetaminophen should not be used for longer than 10 days.

Dosing
The oral dose for adults is 325 to 650 mg every 4 to 6 hours. The maximum daily dose is 4 grams. The oral dose for a child is based on the child's age, and the range is 40-650 mg every 4 hours. When administered as a suppository, the adult dose is 650 mg every 4 to 6 hours. For children, the dose is 80-325 mg every 4 to 6 hours depending on age.

Pregnancy
Acetaminophen is used in all stages of pregnancy and is the drug of choice for short-term treatment of fever and minor pain during pregnancy.

Nursing Mothers
Acetaminophen is excreted in breast milk in small quantities. However, acetaminophen use by the nursing mother appears to be safe.

Warning
Taking too much acetaminophen can cause liver damage, sometimes serious enough to require liver transplantation or cause death. You might accidentally take too much acetaminophen if you do not follow the directions on the prescription or package label carefully, or if you take more than one product that contains acetaminophen. To be sure that you take acetaminophen safely, you should: not take more than one product that contains acetaminophen at a time. Read the labels of all the prescription and nonprescription medications you are taking to see if they contain acetaminophen. Be aware that abbreviations such as APAP, AC, Acetaminophn, Acetaminoph, Acetaminop, Acetamin, or Acetam. may be written on the label in place of the word acetaminophen. Ask your doctor or pharmacist if you don't know if a medication that you are taking contains acetaminophen. take acetaminophen exactly as directed on the prescription or package label. Do not take more acetaminophen or take it more often than directed, even if you still have fever or pain. Ask your doctor or pharmacist if you do not know how much medication to take or how often to take your medication. Call your doctor if you still have pain or fever after taking your medication as directed. be aware that you should not take more than 4000 mg of acetaminophen per day. If you need to take more than one product that contains acetaminophen, it may be difficult for you to calculate the total amount of acetaminophen you are taking. Ask your doctor or pharmacist to help you. tell your doctor if you have or have ever had liver disease. tell your doctor if you drink 3 or more alcoholic drinks every day. Talk to your doctor about the safe use of alcohol while you are taking acetaminophen. stop taking your medication and call your doctor right away if you think you have taken too much acetaminophen, even if you feel well.

Talk to your pharmacist or doctor if you have questions about the safe use of acetaminophen or acetaminophen-containing products.

What special precautions should I follow?

The primary precaution in children's therapy is to watch the dosage carefully and follow the label instructions only. Acetaminophen for children comes in two strengths. Children's acetaminophen contains low concentrations of the drug, 160 milligrams in a teaspoonful of solution. The infant drops contain a much higher concentration of acetaminophen, 100 milligrams in 20 drops, equal to 500 milligrams in a teaspoonful. The infant drops should never be given by the teaspoonful. Before taking acetaminophen, tell your doctor and pharmacist if you are allergic to acetaminophen, any other medications, or any of the ingredients in the product. Ask your pharmacist or check the label on the package for a list of ingredients. tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, or herbal products you are taking or plan to take. Be sure to mention anticoagulants ('blood thinners') such as warfarin (Coumadin); isoniazid (INH); certain medications for seizures including carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); medications for pain, fever, coughs, and colds; and phenothiazines (medications for mental illness and nausea). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. tell your doctor if you have any serious medical condition. tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking acetaminophen, call your doctor. if you drink three or more alcoholic beverages every day, ask your doctor if you should take acetaminophen. Ask your doctor or pharmacist about the safe use of alcoholic beverages while taking acetaminophen. you should know that combination acetaminophen products for cough and colds that contain nasal decongestants, antihistamines, cough suppressants, and expectorants should not be used in children younger than 2 years of age. Use of these medications in young children can cause serious and life-threatening effects or death. In children 2 through 11 years of age, combination cough and cold products should be used carefully and only according to the directions on the label. if you have phenylketonuria (PKU, a inherited condition in which a special diet must be followed to prevent mental retardation), you should know that some brands of acetaminophen chewable tablets may be sweetened with aspartame. a source of phenylalanine.

Parental Concerns Acetaminophen is very safe when used properly. While most precautions are intended to reduce the risk of overdose, parents should not try to reduce the risk by giving a lower than normal dose. Children should not suffer pain if it can be safely treated.

Why is this medication prescribed?

Acetaminophen is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches, and reactions to vaccinations (shots), and to reduce fever. Acetaminophen may also be used to relieve the pain of osteoarthritis (arthritis caused by the breakdown of the lining of the joints). Acetaminophen is in a class of medications called analgesics (pain relievers) and antipyretics (fever reducers). It works by changing the way the body senses pain and by cooling the body.

Other uses for this medicine

Acetaminophen may also be used in combination with aspirin and caffeine to relieve the pain associated with migraine headache.

How should I use acetaminophen?

Use acetaminophen exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Do not take more acetaminophen than is recommended. An overdose can damage your liver or cause death. One acetaminophen pill, suppository, or packet of granules may contain up to 650 mg of acetaminophen. Know the amount of acetaminophen in the specific product you are taking. If you are treating a child, use a pediatric form of acetaminophen. Carefully follow the dosing directions on the medicine label. Do not give the medication to a child younger than 2 years old without the advice of a doctor. The chewable tablet must be chewed thoroughly before you swallow it.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

This medication is usually taken as needed. If your doctor has told you to take acetaminophen regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Important information about acetaminophen

There are many brands and forms of acetaminophen available and not all brands are listed on this leaflet. Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Know the amount of acetaminophen in the specific product you are taking. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take acetaminophen. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen. Ask a doctor or pharmacist if it is safe for you to take this medicine if you have liver disease or a history of alcoholism. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP.

What other drugs will affect acetaminophen?

There may be other drugs that can interact with acetaminophen. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Acetaminophen may interact with a variety of other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Among the drugs that may interact with acetaminophen are the following: alcohol nonsteroidal anti-inflammatory drugs (NSAIDs) such as Motrin oral contraceptives the antiseizure drug phenytoin (Dilantin) the blood-thinning drug warfarin (Coumadin) the cholesterol-lowering drug cholestyramine (Questran) the antibiotic Isoniazid zidovudine (Retrovir, AZT) Cholestyramine (Questran) reduces the effect of acetaminophen by decreasing its absorption into the body from the intestine. Therefore, acetaminophen should be administered 3 to 4 hours after cholestyramine or one hour before cholestyramine . Acetaminophen doses greater than 2275 mg per day may increase the blood thinning effect of warfarin (Coumadin) by an unknown mechanism. Therefore, prolonged administration or large doses of acetaminophen should be avoided during warfarin therapy. Check with a physician or pharmacist before combining acetaminophen with any other prescription or nonprescription (over-the-counter) medicine. Acetaminophen is generally safe when taken as directed. Acetaminophen is commonly mixed with other ingredients as part of combinations intended for colds, influenza, and other

conditions. Parents should read the labels carefully in order to avoid giving an overdose of acetaminophen to their child. They need to be particularly cautious about liquid medicines that contain acetaminophen and alcohol.

Compare Acetaminophen with other medications

Fever Muscle Pain Pain Sciatica

Make sure your hands are dry when handling the acetaminophen disintegrating tablet. Place the tablet on your tongue. It will begin to dissolve right away. Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing. Stop using acetaminophen and call your doctor if: you still have a fever after 3 days of use; you still have pain after 7 days of use (or 5 days if treating a child); you have a skin rash, ongoing headache, or any redness or swelling; or if your symptoms get worse, or if you have any new symptoms. Urine glucose tests may produce false results while you are taking acetaminophen. Talk to your doctor if you are diabetic and you notice changes in your glucose levels during treatment.

Adverse effects
In recommended doses, the side effects of paracetamol are mild to non-existent. In contrast to aspirin, it is not a blood thinner (and thus may be used in patients where coagulation is a worry), and it does not cause gastric irritation. Comparing with Ibuprofen which has adverse effects like diarrhea, vomiting and abdominal pain, Acetaminophen is well tolerated with fewer side effects. Prolonged daily use increases the risk of upper gastrointestinal complications such as stomach bleeding, and may cause kidney or liver damage. Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage. Until 2010 paracetamol was believed to be safe in pregnancy (as it does not affect the closure of the fetal ductus arteriosus as NSAIDs can.) However, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn. Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood although recent research show some evidence that paracetamol can ease psychological pain. Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. Paracetamol use for fever in the first year of life was associated with an increase in the incidence of asthmatic symptoms at 67 years, and that paracetamol use, both in the first year of life and in children aged 67 years, was associated with an increased incidence of rhinoconjunctivitis and eczema. Paracetamol remains a safe and appropriate choice of analgesic in children. Chronic users of acetaminophen may have a higher risk of developing blood cancer.

What side effects can this medication cause?

Some side effects can be serious. If you experience any of the following symptoms, stop taking acetaminophen and call your doctor immediately: Acetaminophen causes few side effects. The most common one is lightheadedness. Some people may experience trembling and pain in the side or the lower back. Allergic reactions do occur in some people, but they are rare. Anyone who develops symptoms such as a rash, swelling, or difficulty breathing after taking acetaminophen should stop taking the drug and get immediate medical attention. Other rare side effects include yellow skin or eyes, unusual bleeding or bruising, weakness, fatigue, bloody or black stools, bloody or cloudy urine, and a sudden decrease in the amount of urine. Overdoses of acetaminophen may cause nausea, vomiting, sweating, and exhaustion. Very large overdoses can cause liver damage. In case of an overdose, parents should get immediate medical attention for their child.When used appropriately, side effects with acetaminophen are rare. The most serious side effect is liver damage due to large doses, chronic use or concomitant use with alcohol or other drugs that also damage the liver. Chronic alcohol use may also increase the risk of stomach bleeding.

Overdose Paracetamol toxicity

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 poison control centers in the US than overdose of any other pharmacological substance. Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment 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 damage to the liver, a liver transplant is often required if damage to the liver becomes severe. There are tablets available (brandname in the UK Paradote) that combine paracetamol with an antidote (methionine), to protect the liver in case of an overdose. In June 2009, a U.S. Food and Drug Administration (FDA) advisory committee recommended that new restrictions should be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage to be consumed at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of paracetamol had been shown to produce alterations in hepatic function. On January 13, 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of these products to warn of the potential risk for severe liver damage. Manufacturers will have three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit. The FDA also is requiring manufacturers to update labels of all prescription combination paracetamol products to warn of the potential risk for severe liver injury.

Classification
Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today. It is classified as a nonsteroidal anti-inflammatory drug (NSAID). Paracetamol has few anti-inflammatory effects in comparison to NSAIDs. However, aspirin, paracetamol and other NSAIDs all act by the same mechanism (inhibition of prostaglandin synthesis) and all show varying levels of analgesic, anti-inflammatory, antipyretic and antiplatelet actions.

Mechanism of action

AM404 - Metabolite of paracetamol

Anandamide - Endogenous cannabinoid To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is considered to be the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. While it has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is high level of peroxides present in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to other NSAIDs can be observed. Because of its selectivity for COX-2 it does not significantly inhibit the production of the proclotting thromboxanes. The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule that is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active. Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming proinflammatory chemicals. This leads to a reduced amount of Prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre. Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolized to AM404, a compound with several actions; what is most important is that it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine. Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid system.

The exact mechanisms by which COX is inhibited in various circumstances is still a subject of discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it has been postulated that further COX variants may exist. A recently discovered COX-1 splice variant termed COX-3 was considered to explain some of the knowledge gap but newer findings do not support the hypothesis that it plays any significant role in the functioning of paracetamol. One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol. However, some research has suggested that, in humans and mice, the COX-3 enzyme is without inflammatory action. Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that is in an inflammatory environment where the concentration of peroxides is high, and the high oxidation state of paracetamol prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc. The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.

Structure and reactivity

Paracetamol molecule polar surface area Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern.[66] The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl 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 electrophilic 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 basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.

Synthesis
In the laboratory, paracetamol is easily prepared by nitrating phenol with sodium nitrate, separating the desired p-nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant p-aminophenol is then acetylated with acetic anhydride. In this reaction, phenol is strongly activating, thus the reaction requires only mild conditions (cf. the nitration of benzene). The industrial process is analogous, but hydrogenation is used instead of the sodium borohydride reduction.

A simpler synthesis by Hoechst-Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement to give the amide.

Demand for paracetamol in the United States was estimated at 30-35 thousand tonnes per year in 1997, equal to the demand from the rest of the world.

Metabolism

Main pathways of paracetamol metabolism (click to enlarge). Pathways shown in blue and purple lead to non-toxic metabolites; the pathway in red leads to toxic NAPQI. Paracetamol is metabolised primarily in the liver, into non-toxic products. Three metabolic pathways are notable: Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[72] Sulfation (sulfate conjugation) may account for 2040%.[72] N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-pbenzo-quinone imine). NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication. Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed to be due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses. At usual doses, NAPQI is quickly detoxified by conjugation. Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated, and, as a consequence, NAPQI accumulates.

Reactions
p-Aminophenol may be obtained by the amide hydrolysis of paracetamol. pAminophenol prepared this way, and related to the commercially available Metol, 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, paminophenol reacts in ammonia solution with a phenol derivate e.g. salicylic acid to form an indophenol dye under oxidization by air.

History

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 A. Cahn and P. Hepp in 1886. But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives.[49] Harmon Northrop Morse had already synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on patients. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, 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 Bayer as a leading pharmaceutical company. Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures," usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes a barbiturate. 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 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. In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established it was just as efficacious an analgesic as its precursor. They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. This led to a "rediscovery" of paracetamol. It has been suggested that contamination of paracetamol with 4aminophenol, the substance from which it was synthesized by von Mering, may be the cause for his spurious findings.

Paracetamol was first marketed in the United States in 1953 by Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers. The best known brand today for paracetamol in the United States, Tylenol, was established in 1955 when McNeil Laboratories started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixirthe word "tylenol" was a contraction of para-acetylaminophenol. In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. 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. 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. The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".

Available forms

Tylenol 500 mg capsules (US)

Panadol 500 mg tablets (AU)

Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, and intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4000 mg. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults, although rare cases of acute liver injury have been linked to amounts lower than 2500 mg per day. Panadol, which is marketed in Africa, Asia, Europe, Central America, and Australasia, is the most widely available brand of paracetamol, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc.), Anacin-3, Tempra, Datril, and Ofirmev. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. Acamol, a brand name for paracetamol produced by Teva Pharmaceutical Industries in Israel, is one of the most widely used drugs in that country. In the Philippines, the largest-selling paracetamol brand is Biogesic, manufactured by the drug giant United Laboratories. Biogesic tablet sales reach nearly a billion units each year in the country alone, not including liquid suspension formats. The brand is also available in most of the ASEAN countries where the drug giant has market presence. In Europe, the most common

brands of paracetamol are Efferalgan and Doliprane. In India, the most common brand of paracetamol is Crocin manufactured by Glaxo SmithKline Asia. In Bangladesh the most popular brand is Napa manufactured by Beximco Pharma. In China paracetamol is sold over the counter as Duyxin'njfn Pin (). Likewise in Japan it is sold under the name Acetaminophen ( Asetoaminofen). In North Korea the DPRK-Swiss joint venture PyongSu Pharma markets the drug as PyongSu Cetamol. In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 810 mg, 15 mg, 30 mg, and 60 mg of codeine, respectively. 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. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol. The efficacy of paracetamol/codeine combinations have been questioned by recent research. Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.

Veterinary use
Paracetamol is extremely toxic to cats. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down, and minute portions of a tablet may prove fatal. Initial symptoms include vomiting, salivation, and discolouration 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 (methemoglobemia and hemolytic anemia). Treatment with N-acetylcysteine, methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol. 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 on veterinary prescription in the UK. It should be administered to dogs only on veterinary advice and with extreme caution. The main effects of toxicity in dogs is liver damage, GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within a few hours of paracetamol ingestion. Paracetamol is also lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.