CHIMIE an II Chemestry Essay about Paracetamol (acetaminophen)

Paracetamol

Paracetamol (INN) ( acetaminophen) is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with non-steroidal antiinflammatory drugs (NSAIDs) and opioid analgesics, paracetamol is used also in the management of more severe pain (such as postoperative pain). While generally safe for human use at recommended doses (1000 mg per single dose and up to 4000 mg per day for adults, up to 2000 mg per day if drinking alcohol), 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. Paracetamol is derived from coal tar, and is part of the class of drugs known as aniline analgesics; it is the only such drug still in use today. 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, Hong Kong, Iran, 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. There is confusion in terminology of Paracetamol (known as Acetaminophen in North America). It should be included in NSAIDS but Paracetamol has very little antiinflammatory effect in many tissues. However aspirin, paracetamol and other NSAIDs all act by the same mechanism (inhibition of PG synthesis) and all show varying levels of analgesic, anti-inflammatory, antipyretic and antiplatelet actions.

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. But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives. 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 wasn't 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 or 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.[7] 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. Bernard Brodie and Julius Axelrod (pictured) demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better tolerated analgesic. 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.[citation needed] 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".

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.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.

Available forms- List of paracetamol brand names

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. Panadol, which is marketed in Africa, Asia, Central America, and Australasia, is the most widely available brand, 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.),Tydenol (Edruc Limited,Bangladesh) Anacin-3, Tempra, and Datril,. 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 popular drugs in that country. 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 some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as cocodamol (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. Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine. Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory activity, so it is not considered to be a non-steroidal anti-inflammatory drug (NSAID).

Mechanism of action
This section may require cleanup to meet Wikipedia's quality standards. Please improve this section if you can. (January 2010). Paracetamol is usually classified along with nonsteroidal antiinflammatory drugs (NSAID),but is not considered one, rather is part of the class of drugs known as aniline analgesics. Like all drugs of this class, its main mechanism of action is the inhibition of cyclooxygenase (COX),[citation needed] an enzyme responsible for the production of prostaglandins, which are important mediators of inflammation, pain and fever. Therefore, all NSAIDs are said to possess anti-inflammatory, analgesic (anti-pain), and antipyretic (anti-fever) properties. The specific actions of each NSAID drug depends upon their pharmacological properties, distribution and metabolism. While paracetamol has analgesic and antipyretic properties comparable to those of aspirin, it fails to exert significant anti-inflammatory action due to paracetamol's susceptibility to the high level of peroxides present in inflammatory lesions.

Anandamidean endogenous cannabinoid However, the mechanism by which paracetamol reduces fever and pain is still debated largely because paracetamol reduces the production of prostaglandins (pro-inflammatory chemicals). Aspirin also inhibits the production of prostaglandins, but, unlike aspirin, paracetamol has little anti-inflammatory action. Likewise, whereas aspirin inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and, because of paracetamol's partial similarity of aspirin's action,[clarification needed] much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways. The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule, which 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 pro-inflammatory chemicals. Thus reducing the amount of Prostaglandin E2 in the CNS and thus lowering the hypothalamic set point in the thermoregulatory centre. Inhibition of another enzyme COX3 is specifically implicated in the case of paracetamol. COX3 is not seen outside the CNS Article text. Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolized to AM404, a compound with several actions; most important, 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, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol loses analgesic effect, suggesting its pain-relieving action is mediated by the endogenous cannabinoid system. One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. This enzyme, when expressed in dogs, 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 in an inflammatory environment, where the concentration of peroxides is high, the oxidation state of paracetamol is high which prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation.

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