Paracetamol

Paracetamol
Systematic (IUPAC) name
N-(4-hydroxyphenyl)acetamide
Identifiers
CAS number 103-90-2
ATC code N02BE01
PubChem CID 1983
DrugBank DB00316
ChemSpider 1906
UNII 362O9ITL9D
ChEBI CHEBI:116450
ChEMBL CHEMBL112
Chemical data
Formula C8H9NO2 
Mol. mass 151.17 g/mol
SMILES eMolecules & PubChem
Physical data
Density 1.263 g/cm³
Melt. point 168 °C (334 °F)
Solubility in water 12.78 [1] mg/mL (20 °C)
Pharmacokinetic data
Bioavailability ~100%
Metabolism 90 to 95% Hepatic
Half-life 1–4 h
Excretion Renal
Therapeutic considerations
Licence data US FDA:[http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Acetaminophen &SearchType=BasicSearch link]
Pregnancy cat. A(AU) B(US) safe
Legal status Unscheduled (AU) GSL (UK) OTC (US)
Routes Oral, rectal, intravenous
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Paracetamol (INN) (, English pronunciation: /ˌpærəˈsɛtəmɒl/) or acetaminophen (English pronunciation: /əˌsiːtəˈmɪnɵfɨn/) (USAN) is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of headaches, other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post surgical pain and providing palliative care in advanced cancer patients.[2] The onset of analgesia is approximately 11 minutes after oral administration of paracetamol,[3] and its half life is 1–4 hours.

While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults, up to 2,000 mg per day if drinking alcohol),[4] acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcohol consumption. 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.[5][6][7][8]

Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today.[9] 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.[10] The words acetaminophen (used in the United States, Canada, Hong Kong, Iran,[11] Colombia and other Latin American countries) and paracetamol (used elsewhere) both come from chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for N-acetyl-para-aminophenol.

The classification of paracetamol, and the terminology used to refer to it, can cause confusion. It is often classified as a nonsteroidal anti-inflammatory drug (NSAID), but paracetamol has few anti-inflammatory effects in many tissues. 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.[12]

History

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.[13] But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives.[9] 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,[14][15] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on patients.[9] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[16] 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.[17] 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.[9]

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.[17] 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.[18] 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.[19][20][21] 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.[22] This led to a "rediscovery" of paracetamol.[9] It has been suggested that contamination of paracetamol with 4-aminophenol, the substance from which it was synthesized by von Mering, may be the cause for his spurious findings.[17]

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.[17] 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 Elixir—the word "tylenol" was a contraction of para-acetylaminophenol.[23] 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.[15] 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.[9]

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".[24]

Structure and reactivity

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.[25] 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

Industrial preparation of paracetamol usually proceeds from nitrobenzene.[26] 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.[27] In this reaction, phenol is strongly activating, thus the reaction requires only mild conditions (cf. the nitration of benzene):