Paracetamol

Paracetamol
Systematic (IUPAC) name
N-(4-hydroxyphenyl)acetamide
Identifiers
CAS number	103-90-2
ATC code	N02BE01
PubChem	1983
DrugBank	APRD00252
ChemSpider	1906
Chemical data
Formula	C8H9NO2
Mol. mass	151.169 g/mol
SMILES	eMolecules & PubChem
Physical data
Density	1.263 g/cm³
Melt. point	169 °C (336 °F)
Solubility in water	14 mg/mL @ 25C [1] mg/mL (20 °C)
Pharmacokinetic data
Bioavailability	almost 100%
Metabolism	90 to 95% Hepatic
Half life	1–4 hours
Excretion	Renal
Therapeutic considerations
Licence data	US
Pregnancy cat.	A(AU) B(US) safe
Legal status	Unscheduled(AU) GSL(UK) OTC(US)
Routes	Oral, rectal, intravenous

Paracetamol (INN) (IPA: /ˌpærəˈsiːtəmɒl, -ˈsɛtə-/) or acetaminophen (USAN) is a widely-used analgesic and antipyretic medication. Derived from coal tar, it is the active metabolite of phenacetin, but unlike phenacetin, paracetamol has not been shown to be carcinogenic in any way. Paracetamol generally is well tolerated, lacks many of the side-effects of aspirin, and is available over-the-counter. It is commonly used for the relief of fever, headaches, and other minor aches and pains. In combination with non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics, paracetamol is used also in the management of more severe pain.^[2] Paracetamol is a major ingredient in numerous cold and flu remedies.

While generally safe for human use at recommended doses, acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same. 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.^[3][4][5][6] This risk is heightened by alcoholism. A 2008 study indicates that Paracetamol given to infants may also be linked to an increased risk of developing asthma in children.^[7][8][9]

The words acetaminophen and paracetamol come from the chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. The brand name Tylenol also derives from this name: para-acetylaminophenol. In some contexts, it is shortened to APAP, for N-acetyl-para-aminophenol.

History

In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark.^[10] Cinchona bark was also used for the extraction of the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was impractical).^[11]

When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878;^[12] however, paracetamol was not used in medical treatment for another 15 years. In 1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time.

Julius Axelrod demonstrated in 1948 that acetanilide degrades into N-acetyl p-aminophenol (i.e., paracetamol), a metabolite that acts as an analgesic but is better tolerated.

In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a condition that decreases the oxygen-carrying capacity of blood and is potentially lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the direct use of paracetamol, since it did not have the toxic effects of acetanilide.^[13]

The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir.^[14]

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 June 1958, a children's formulation, Panadol Elixir, was released.

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.

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".

Chemistry

Structure and reactivity

The paracetamol molecule

Polar surface area of the paracetamol molecule

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.

Synthesis

From the starting material phenol, paracetamol can be made in the following manner:

1. Phenol is nitrated using sulfuric acid and sodium nitrate (as phenol is highly activated, its nitration requires very mild conditions compared to the oleum-fuming nitric acid mixture required to nitrate benzene).
2. The para isomer is separated from the ortho isomer by fractional distillation (there will be little of meta, as OH is o-p directing).
3. The 4-nitrophenol is reduced to 4-aminophenol using a reducing agent such as sodium borohydride in basic medium.
4. 4-aminophenol is reacted with acetic anhydride to give paracetamol.

Note that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: Lack of stereocenters means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also available.

Available forms

Main article: List of paracetamol brand names

Tablets are the most common form of paracetamol.

500 mg Panadol suppositories

Panadol, which is marketed in Europe, 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.), 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.

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 approximately 1/8 grain, approximately 1/4 grain, approximately 1/2 grain, and approximately 1 grain of codeine, respectively. A US grain is 64.78971 milligrams—this is usually rounded in manufacture down to a multiple of 5 mg (so that a #3 contains 30 mg, and a #4 contains 60 mg, while a #1 may be 8 mg or 10 mg depending on manufacturer). 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 generics 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.

It is commonly administered in tablet, liquid suspension, suppository, intravenous, or intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults.

Mechanism of action

The mechanism by which paracetamol reduces fever and pain is still a source of debate.^[16] The reason for this confusion has largely been due to the fact that 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, much research has focused on whether paracetamol also inhibits COX. It is now clear, however, that paracetamol acts via (at least) two pathways.^{[17][18][19][20]}

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.^[21][22] It has been shown that paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.^[18][23]

Further research has shown that paracetamol also modulates the endogenous cannabinoid system.^[24] 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, similarly to the anesthetics lidocaine and procaine.^[25] 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 no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system.^[26]

One theory holds that paracetamol works by inhibiting the COX-3 isoform of the cyclooxygenase 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.^[27] However, some research has suggested that in humans and mice, the COX-3 enzyme is without inflammatory action.^[17] Another possibility is that paracetamol is able to block cycloxygenase 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 but instead acts in the CNS to reduce temperature etc where the environment is not oxidative.^[27] The exact mechanism by which paracetamol is believed to affect COX-3 is still disputed by some research.

Metabolism

The reactions involved in paracetamol metabolism

Paracetamol is metabolised primarily in the liver, where its major metabolites include inactive sulfate and glucuronide conjugates, which are excreted by the kidneys. Only a small, yet significant amount is metabolised via the hepatic cytochrome P450 enzyme system (its CYP2E1 and CYP1A2 isoenzymes), which is responsible for the toxic effects of paracetamol due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI).^[28] There is a great deal of polymorphism in the P450 gene, and genetic polymorphisms in CYP2D6 have been studied extensively. The population can be divided into "extensive", "ultrarapid", and "poor metabolizers" depending on their levels of CYP2D6 expression. CYP2D6 may also contribute to the formation of NAPQI, albeit to a lesser extent than other P450 isozymes, and its activity may contribute to paracetamol toxicity, in particular, in extensive and ultrarapid metabolizers and when paracetamol is taken at very large doses.^[29]

The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself. At usual doses in persons with a common phenotype, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.^[28] This route becomes saturated following overdose.

Comparison with NSAIDs

Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory activity, and so it is not considered to be a non-steroidal anti-inflammatory drug (NSAID).

Efficacy

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.^[30] However, a randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen gives greater relief of pain than the standard dose of paracetamol.^[31]

Adverse effects

In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However, some studies have shown that high dose-usage (greater than 2,000 mg per day) does increase the risk of upper gastrointestinal complications such as stomach bleeding.^[32]

Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus arteriosus as NSAIDs can. Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses.

Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. While paracetamol and NSAIDs may damage the liver, they do not pose a large risk of addiction, dependence, tolerance, and withdrawal.

Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.^[33]

A 2008 preliminary case-control study based on a parent survey presented evidence that paracetamol following MMR vaccination is apparently associated with development of autism in children aged 1–5 years. The effect seemed to appear only in children who show some post-vaccination regression together with other post-vaccination sequelae such as fever, and it was not seen with other painkillers such as ibuprofen. The effect has not been independently confirmed.^[34]

Toxicity

Main articles: Paracetamol toxicity and Analgesic nephropathy

Excessive use of paracetamol can damage multiple organs, especially the liver and kidney. In both organs, toxicity from paracetamol is not from the drug itself but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). In the liver, the cytochrome P450 enzymes CYP2E1 and CYP3A4 are primarily responsible for the conversion of paracetamol to NAPQI. In the kidney, cyclooxygenases are the principal route by which paracetamol is converted to NAPQI.^[35]

Paracetamol overdose leads to the accumulation of NAPQI, which undergoes conjugation with glutathione. Conjugation depletes glutathione, a natural antioxidant. This in combination with direct cellular injury by NAPQI, leads to cell damage and death. These injuries are known as paracetamol hepatotoxicity and analgesic nephropathy in the liver and kidney, respectively.

Signs and symptoms of phenacetin toxicity may initially be absent or vague. Untreated, overdose can lead to liver failure and death within days. Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.^[6][36] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.^[37]

Effects on animals

Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down, and minute portions of a tablet may prove fatal.^[38] Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. After around two days, liver damage is evident, typically giving rise to jaundice. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methaemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation. Effective treatment is occasionally possible for small doses, but must be extremely rapid.

In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration than NSAIDs. It should be administered only on veterinary advice. A paracetamol-codeine product (trade name Pardale-V)^[39] licensed for use in dogs is available on veterinary prescription in the UK.^[40]

Any cases of suspected ingestion in cats or overdose in dogs should be taken to a veterinarian immediately for detoxification.^[41] The effects of toxicity can include liver damage, haemolytic anaemia, oxidative damage to the red blood cells and bleeding tendencies. There are no home remedies, and the amount of irreversible liver failure is dependent on how quickly veterinary intervention begins. Treatment of paracetamol overdose by a veterinarian may involve the use of supportive fluid therapy, acetylcysteine (trade name Mucomyst), methionine, or S-adenosyl-L-methionine (SAMe) to slow liver damage, and cimetidine (trade name Tagamet) to protect against gastric ulceration. Once liver damage has occurred, it cannot be reversed. ^[42] Vitamin C can be used to aid in the conversion of methemoglobine back to hemoglobine (6 x 30mg/kg every 6 hours).

Paracetamol is also lethal to snakes, and has been used in attempts to control the brown tree snake (Boiga irregularis) in Guam.^[43]

See also

• List of paracetamol brand names
• Tylenol scare
• AM404
• NAPQI
• Acetaminophen toxicity

Notes and references

External links

• List of Paracetamol synonyms
• Paracetamol Information Centre
  • History of paracetamol
• U.S. Patent 6,126,967
• The Julius Axelrod Papers