Tylenol

アセトアミノフェン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/27 22:35:34」(JST)

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タイレノール」

タイレノール（Tylenol）は、ジョンソン・エンド・ジョンソンが販売するアセトアミノフェンを単一成分とする解熱鎮痛剤である。

アセトアミノフェンは胃を刺激しないことから空腹時にも使用できることが特徴である（ただし、かぜによる悪寒・発熱時を除く）。

概要

米マクニール研究所（1959年にジョンソン・エンド・ジョンソンによって買収）はアスピリンの副作用に対して、1953年にアセトアミノフェンを含む鎮痛剤の開発を開始。1955年に小児用にタイレノール・エリクシールを発売する。

はじめは小児用として売り出されたものだったが、これがすぐに大人にも支持を得て、現在アメリカでは鎮痛剤市場の約35%をタイレノールが占めるに至る。

タイレノールというブランド名は、アセトアミノフェンの正式な化学名、「N-acetyl-para-aminophenol」から取ったものである。

アメリカ国内向けのボトルは、子供が容易に開けられないようなボトルとなっている。開け方はキャップをねじって、キャップの矢印をボトルの矢印と合わせ、キャップを引き上げる。キャップを引き上げる際、かなりの力を要するので、布巾などで包んで引き上げると良い。

日本国内における展開

日本で販売されているOTC薬品の中で唯一のアセトアミノフェンの単一製剤である。

当初武田薬品工業がライセンスを得て2000年9月に発売。発売にあたっては他社商品を列挙した比較広告を打ち出したものの、シェアを獲得することができず、2004年10月にジョンソン・エンド・ジョンソンは提携を解消し直販とした。 この頃から片仮名から英語のブランドロゴをメインにしたパッケージデザインに変更された。当時のテレビCMは安田成美や山岡由実が出演していた。

なお、2012年10月からジョンソン・エンド・ジョンソンの一般用医薬品全ブランドが武田薬品工業からの販売に変更されたため、販売提携ながら再び武田薬品工業がタイレノールの販売を行うこととなった。

種類

日本発売の製剤は次のとおり。

• タイレノールA【第2類医薬品】 - 楕円形のカプセル型の錠剤（大人（15歳以上）専用。製造販売元：東亜薬品）

成分（1錠中）：アセトアミノフェン300mg

販売終了品

• タイレノールFD【第2類医薬品】 - かみくだくか、口中で溶かして水なしで服用できるミント味のチュアブルタイプの錠剤（大人（15歳以上）専用。製造販売元：ダイト）

成分（2錠中）：アセトアミノフェン300mg

口中で溶ける平均時間：約30秒

• タイレノールFD小児用【第2類医薬品】 - かみくだくか、口中で溶かして水なしで服用できるミント味のチュアブルタイプの錠剤（5歳以上14歳未満。製造販売元：ダイト）

成分（1錠中）アセトアミノフェン50mg

1982年タイレノール殺人事件

1982年9月29日、シカゴ近郊のイリノイ州エルクグローブ村の12歳の少女が「タイレノール Extra Strength（カプセル）」を服用したところ混入されていたシアン化合物によって死亡。以後計5瓶のタイレノールによって計7名の死者を出した。この他に毒物が混入された3瓶が回収された。事件は未解決で、この後シカゴ周辺では1986年エキセドリン殺人事件のような多くの模倣事件が発生した。

この事件でジョンソン・エンド・ジョンソンは「タイレノールにシアン化合物混入の疑いがある」とされた時点で迅速に消費者に対し、125,000回に及ぶTV放映、専用フリーダイヤルの設置、新聞の一面広告などの手段で回収と注意を呼びかけた（1982年10月5日、タイレノール全製品のリコールを発表）。およそ3100万本の瓶を回収するにあたり約1億USドル（当時の日本円で約277億円）の損失が発生。事件発生後、毒物の混入を防ぐため「3重シールパッケージ」を開発し発売。この徹底した対応策により1982年12月（事件後2ヶ月）には、事件前の売上の80%まで回復した。

ジョンソン&ジョンソンには「消費者の命を守る」ことを謳った「我が信条」（Our Credo）という経営哲学があり、社内に徹底されていた。緊急時のマニュアルが存在しなかったにもかかわらず迅速な対応ができたのはこのためである。

この事件は危機管理における対応策の定石として認識されている。

脚注

外部リンク

• タイレノール・ブランドサイト（ジョンソン・エンド・ジョンソン）

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Paracetamol

Systematic (IUPAC) name
N-(4-hydroxyphenyl)ethanamide N-(4-hydroxyphenyl)acetamide
Clinical data
Pronunciation	Paracetamol /ˌpærəˈsiːtəmɒl/ or /ˌpærəˈsɛtəmɒl/ Acetaminophen i/əˌsiːtəˈmɪnəfᵻn/
Trade names	Tylenol, Panadol, others
AHFS/Drugs.com	monograph
MedlinePlus	a681004
Licence data	US FDA: Acetaminophen
Pregnancy category	AU: A US: C (Risk not ruled out) Not tested but seems to be safe
Legal status	AU: Unscheduled UK: General sales list (GSL, OTC) US: OTC
Routes of administration	Oral, rectal, intravenous
Pharmacokinetic data
Bioavailability	63–89%
Protein binding	10–25%
Metabolism	Predominantly in the liver
Metabolites	APAP gluc, APAP sulfate, NAPQI, APAP-GSH, APAP-cys
Biological half-life	1–4 hours
Excretion	Urine (85–90%)
Identifiers
CAS Number	103-90-2 Y
ATC code	N02BE01
PubChem	CID 1983
IUPHAR/BPS	5239
DrugBank	DB00316 Y
ChemSpider	1906 Y
UNII	362O9ITL9D Y
KEGG	D00217 Y
ChEBI	CHEBI:46195 Y
ChEMBL	CHEMBL112 Y
PDB ligand ID	TYL (PDBe, RCSB PDB)
Chemical data
Formula	C8H9NO2
Molar mass	151.163 g/mol
SMILES CC(NC1=CC=C(O)C=C1)=O
InChI InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) Y Key:RZVAJINKPMORJF-UHFFFAOYSA-N Y
Physical data
Density	1.263 g/cm3
Melting point	169 °C (336 °F)
Boiling point	420 °C (788 °F)
Solubility in water	12.78 mg/mL (20 °C)
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Paracetamol, also known as acetaminophen or APAP, is a medication used to treat pain and fever. It is typically used for mild to moderate pain. Evidence of benefit in fever for children is poor. It is often sold in combination with other ingredients such as in many cold medications. In combination with opioid pain medication, paracetamol is used for more severe pain such as cancer pain and after surgery. It is typically used either by mouth or rectally but is also available intravenously. Effects last between two and four hours.

Paracetamol is generally safe at recommended doses. Serious skin rashes may rarely occur. Too high a dose can result in liver failure. It appears to be safe during pregnancy and when breastfeeding. In those with liver disease, it may still be used but lower doses should be taken. Paracetamol is classified as a mild analgesic. It does not have significant anti-inflammatory activity and how it works is not entirely clear.

Paracetamol was discovered in 1877. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Paracetamol is available as a generic medication with trade names including Tylenol and Panadol among others. The wholesale price is less than 0.01 USD per dose. In the United States it costs about 0.04 USD per dose.

Medical uses

Fever

Paracetamol is used for reducing fever in people of all ages. The World Health Organization (WHO) recommends that paracetamol be used to treat fever in children only if their temperature is greater 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 ibuprofen.

Pain

Paracetamol is used for the relief of mild to moderate pain.

Osteoarthritis

The American College of Rheumatology 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 osteoarthritis.

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen, 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 analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin due to concerns with bleeding with aspirin.

Low back pain

Based on a systematic review, paracetamol is recommended by the American College of Physicians and the American Pain Society as a first-line treatment for low back pain. However other systematic reviews concluded that evidence for its efficacy is lacking.

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 migraine headache. In the treatment of acute migraine, it is superior to placebo, with 39% of people experiencing pain relief at 1 hour compared to 20% in the control group.

Postoperative pain

Paracetamol, when combined with NSAIDs, may be more effective for treating postoperative pain than either paracetamol alone or NSAIDs alone.

Other

The efficacy of paracetamol when used in combination with weak opioids (such as codeine) improved for approximately 50% of people but increases in the number experiencing side effects. Combination drugs of paracetamol and strong opioids like morphine improve analgesic effect.

The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of common pain conditions including dental pain, postpartum pain, and headache.

Adverse effects

Healthy adults taking regular doses of up to 4,000 mg a day show little evidence of toxicity (although some researchers disagree). They are more likely to have abnormal liver function tests, but the significance of this is uncertain.

Liver damage

Acute overdoses of paracetamol can cause potentially fatal liver damage. According to the US Food and Drug Administration, "Acetaminophen can cause serious liver damage if more than directed is used." and in 2011 the FDA required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury and launched a public education program to help consumers avoid overdose. The risk may be heightened by frequent consumption of alcohol. 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. According to the FDA, in the United States there were "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25 percent of the emergency department visits, 10 percent of the hospitalizations, and 25 percent of the deaths."

Paracetamol is metabolised by the liver and is hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and are very likely in chronic alcoholics or patients with liver damage. Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such as stomach bleeding when high doses are taken chronically. Kidney damage is seen in rare cases, most commonly in overdose. The Food and Drug Administration has warned doctors against prescribing paracetamol/narcotic combinations whose dosages exceed 325 mg of paracetamol due to hepatoxicity risks of greater magnitude than the therapeutic benefits conferred.

Skin reactions

On August 2, 2013, the U.S. Food and Drug Administration (FDA) issued a new warning about paracetamol. It stated that the drug could cause rare, and possibly fatal, skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis. 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

There is an association between paracetamol use and asthma but the evidence suggests that this likely reflects confounders rather than a causal role. A 2014 review found that among children the association disappeared when respiratory infections were taken into account.

As of 2014, the American Academy of Pediatrics and the National Institute for Health and Care Excellence (NICE) 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 antithrombotic), and thus may be used in patients where failure of blood coagulation is a concern; and it does not cause gastric irritation. However, paracetamol does not help reduce inflammation, while aspirin does. Compared to ibuprofen—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 Reye's syndrome in children with viral illnesses.

Paracetamol when taken recreationally with opioids may cause hearing loss.

Overdose

Main article: Paracetamol toxicity

Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure 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 between 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 poison control centers in the US than overdose of any other pharmacological substance. Toxicity of paracetamol is believed to be due to its quinone metabolite.

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 or at least decrease the possible damage to the liver, a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment nomogram (one for patients 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. Kidney failure is also a possible side effect.

There were tablets available until 2004 (brand-name in the UK Paradote) that combined paracetamol with an antidote (methionine), 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 compounding pharmacy to make a similar drug mix for at-risk patients.

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 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.

In January 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 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 Medicines and Healthcare products Regulatory Agency 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 pregnancy. Additionally, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.

Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma. It is also associated with an increase in ADHD but it is unclear whether the relationship is causal. Despite these concerns, paracetamol remains the recommended medication for pain and fever during pregnancy.

Chemical properties

Paracetamol molecule polar surface area

Paracetamol electron map electrostatic 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. 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.

Paracetamol is part of the class of drugs known as "aniline 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.

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 the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes. 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 the high level of peroxides present in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to NSAIDs can be observed.

An article in Nature Communications from researchers in London, UK and Lund, Sweden in November 2011 has found a hint to the analgesic mechanism of paracetamol, being that the metabolites of paracetamol e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain.

This conclusion has been contested in a new hypothesis paper on how paracetamol might act. The author concedes that NAPQI is the active metabolite but that this reactive compound should react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that it happens to encounter. It is suggested that thiol groups in cysteine proteases, e.g. the proteases that take part in the processing of procytokines, such as those generating IL-1β and IL-6, might be the targets giving rise to overall analgesic effects.

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 oxidised is the COX enzyme highly active. Paracetamol reduces the oxidised form of the COX enzyme, preventing it from forming pro-inflammatory chemicals. This leads to a reduced amount of prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.

Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes and, because paracetamol's action is partially similar to aspirin's, much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.

The exact mechanisms by which COX is inhibited in various circumstances are 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. One theory holds that paracetamol works by inhibiting the COX-3 isoform—a COX-1 splice variant—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 and paracetamol's blockage of it is not significant in its functioning in humans.

Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that, in an inflammatory environment where the concentration of peroxides is high, the high oxidation state of paracetamol prevents its actions. This idea 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.

Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolised to AM404, a compound with several actions; what is most important is that it inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide reuptake lowers synaptic levels of anandamide and results in more activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). By inhibiting anandamide reuptake, levels in the synapse remain high and are able to desensitise the TRPV1 receptor much like capsaicin. Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine. Both of these actions by themselves have been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, when cannabinoid receptors are blocked with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid system. Spinal TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and Δ9-tetrahydrocannabinol in mice.

Increase of social behavior in mice dosed with paracetamol (which corresponds to a reduction of social rejection response in humans) does not appear to be due to cannabinoid receptor type 1 activity. It may result from serotonin receptor agonism.

Pharmacokinetics

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.

After oral administration it is rapidly absorbed by the GI tract; its volume of distribution is roughly 50 L. The concentration in serum after a typical dose of paracetamol usually peaks below 30 µg/ml, which equals 200 µmol/L. After 4 hours the concentration is usually less than 10 µg/mL, which equals 66 µmol/L.

Paracetamol is metabolised primarily in the liver, into toxic and non-toxic products. Three metabolic pathways are notable:

• Glucuronidation (45-55%)
• Sulfation (sulfate conjugation) accounts for 20–30%.
• N-hydroxylation and dehydration, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolises paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone imine) (also known as N-acetylimidoquinone). 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 CYP3A4. At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.

Synthesis

Original (Boots) method

The original method for production involves the nitration of phenol with sodium nitrate gives a mixture of two isomers, from which the wanted 4-nitrophenol (bp 279 °C) can easily be separated by steam distillation. In this electrophilic aromatic substitution reaction, phenol's oxygen is strongly activating, thus the reaction requires only mild conditions as compared to nitration of benzene itself. The nitro group is then reduced to an amine, giving 4-aminophenol. Finally, the amine is acetylated with acetic anhydride. Industrially direct hydrogenation is used, but in the laboratory scale sodium borohydride serves.

Green(er) synthesis

An alternative industrial synthesis developed 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.

Direct synthesis

More recently (2014) a "one-pot" synthesis from hydroquinone has been described before the Royal Society of Chemistry. The process may be summarized as follows:

Hydroquinone, ammonium acetate, and acetic acid are 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

4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. 4-Aminophenol 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, 4-aminophenol 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 metabolised 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. Harmon Northrop Morse had already synthesised 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.

Paracetamol is the active metabolite of phenacetin and acetanilide, both once popular as analgesics and antipyretics in their own right. However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered carcinogenic 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 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 that 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 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 4-aminophenol, 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, aspirin, and caffeine. Reports in 1951 of three users stricken with the blood disease agranulocytosis 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 Sterling-Winthrop Co. 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 Tylenol Elixir by McNeil Laboratories. 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. 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. In 1988 Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.

Available without a prescription since 1959, it has since become a common household drug. Patents 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 (USAN) and Japan (JAN); paracetamol is used in international venues (INN, AAN, BAN). In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as APAP, for acetyl-para-aminophenol.

The word acetaminophen is also used in Canada Venezuela, and Colombia. Both come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol.

Available forms

See also: Paracetamol brand names

Tylenol 500 mg capsules

Panadol 500 mg tablets

For comparison: The pure drug is a white crystalline powder.

Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, intramuscular and effervescent 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 is generally 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.

In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN) 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 dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine, and the calmative doxylamine succinate is also available. 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.

Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient, such as ascorbic acid, caffeine, chlorpheniramine maleate, or guaifenesin is added to this combination.

When marketed in combination with diphenhydramine hydrochloride, 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 restless leg syndrome.

Controversy

In September 2013 an episode of This American Life entitled "Use Only as Directed" highlighted deaths from Paracetamol overdose. This report was followed by two reports by ProPublica 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 glucuronyl transferase enzymes 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, 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.

Dogs

Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported 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 effect of toxicity in dogs is liver damage, and GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within a 2 hours of paracetamol ingestion.

Snakes

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. Doses of 80 mg are inserted into dead mice scattered by helicopter.

References

External links

• Pharmacy and Pharmacology portal
• Paracetamol at Chemsynthesis
• Paracetamol International Chemical Safety Cards
• The Julius Axelrod Papers
• FDA: Safe Use of Over-the-Counter Pain Relievers/Fever Reducers
• FDA: Consumer Update "Acetaminophen and Liver Injury: Q and A for Consumers" (link)
• FDA: Consumer Update "Acetaminophen and Liver Injury: Q and A for Consumers" (PDF)
• U.S. National Library of Medicine: Drug Information Portal–Paracetamol
• Acetaminophen bound to proteins in the PDB

UpToDate Contents

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• 1. 成人におけるアセトアミノフェン（パラセタモール）中毒：病態生理、症状、および診断 acetaminophen paracetamol poisoning in adults pathophysiology presentation and diagnosis
• 2. 小児および思春期の患者におけるアセトアミノフェン（パラセタモール）中毒のマネージメント management of acetaminophen paracetamol poisoning in children and adolescents
• 3. 小児および思春期の患者における アセトアミノフェン（パラセタモール）中毒の臨床症状および診断 clinical manifestations and diagnosis of acetaminophen paracetamol poisoning in children and adolescents
• 4. 癌疼痛のマネージメント：アセトアミノフェンおよび非ステロイド性抗炎症剤の使用 cancer pain management use of acetaminophen and nonsteroidal antiinflammatory drugs
• 5. 成人におけるアセトアミノフェン（パラセタモール）中毒：治療 acetaminophen paracetamol poisoning in adults treatment

English Journal

• A zeolite modified carbon paste electrode as useful sensor for voltammetric determination of acetaminophen.

• Ahmadpour-Mobarakeh L1, Nezamzadeh-Ejhieh A2.
• Materials science & engineering. C, Materials for biological applications.Mater Sci Eng C Mater Biol Appl.2015 Apr;49:493-9. doi: 10.1016/j.msec.2015.01.028. Epub 2015 Jan 8.
• The voltammetric behavior of a carbon paste electrode modified with Co(II)-exchanged zeolite A (Co(II)-A/ZMCPE) for determination of acetaminophen was studied. The proposed electrode showed a diffusion controlled reaction with the electron transfer rate constant (Ks) of 0.44s(-1) and charge transfer
• PMID 25686976

• Supra-spinal FAAH is required for the analgesic action of paracetamol in an inflammatory context.

• Dalmann R1, Daulhac L1, Antri M2, Eschalier A3, Mallet C4.
• Neuropharmacology.Neuropharmacology.2015 Apr;91:63-70. doi: 10.1016/j.neuropharm.2014.11.006. Epub 2014 Nov 21.
• Paracetamol (acetaminophen) is the most commonly used analgesic in the world. Recently, a new view of its action has emerged: that paracetamol would be a pro-drug that should be metabolized by the FAAH enzyme into AM404, its active metabolite. However, this hypothesis has been demonstrated only in n
• PMID 25448494

• Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers.

• Honmore V1, Kandhare A, Zanwar AA, Rojatkar S, Bodhankar S, Natu A.
• Pharmaceutical biology.Pharm Biol.2015 Apr;53(4):571-81. doi: 10.3109/13880209.2014.934382. Epub 2014 Oct 23.
• Abstract Context: Acetaminophen (APAP) leads to severe hepatic and renal necrosis and thus causes significant clinical problems. Artemisia pallens Walls ex D.C. (Asteraceae) possesses various pharmacological properties such as antidiabetic, antioxidant, analgesic, and anti-inflammatory activity.OBJE
• PMID 25339313

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• Headache & Pain Relief | TYLENOL®

Information on Tylenol-brand products for children and adults.

Related Pictures

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★リンクテーブル★

リンク元	「アセトアミノフェン」
関連記事	「tylenol」

「アセトアミノフェン」

　　[★]

英

acetaminophen APAP

同

パラセタモール paracetamol

商

Tempra、カロナール、ピリナジン、アトミフェン、アニルーメ、アフロギス、ピレチノール、パラセタ、ナパ、コカール、サールツー、カルジール、(小児坐薬)アンヒバ、(小児坐薬)アルピニー。(サリチルアミド、アセトアミノフェン、カフェイン、クロルフェニラミン)ペレックス、ネオアムノール配合、LL配合。(サリチルアミド、アセトアミノフェン、カフェイン、プロメタジン)PL配合顆粒、マリキナ配合顆粒、ホグス配合顆粒、ピーエイ配合、セラピナ配合、トーワチーム配合、サラザック配合顆粒。(ジプロフィリン、ジヒドロコデイン、dl-メチルエフェドリン、ジフェンヒドラミン、アセトアミノフェン、ブロモバレリル尿素)カフコデN配合。(トラマドール、アセトアミノフェン)トラムセット配合。(イソプロピルアンチピリン、アセトアミノフェン、アリルイソプロピルアセチル尿素、カフェイン)SG配合顆粒

(第2類医薬品)タイレノール Tylenol

関

アセトアミノフェン中毒

• NSAIDs

• 非NSAID

• 酸性

• アニリン系(非ピリン系)

• 解熱薬・鎮痛薬。抗炎症作用はない！！
• 消化管に対する副作用はアスピリンよりかなり少ない。
• 小児の解熱の第一選択薬　←　ex. インフルエンザ患児にアスピリンを投与しReye syndromeの発症

動態

• CYP2E1で分解される

副作用

• ピリン系より副作用が少ない
• 腎障害

• アセトアミノフェン中毒

「tylenol」

　　[★]

同

Tempra, Tylenol

関

Acetaminophen