Paracetamol

Structural formula
General
Non-proprietary name	Paracetamol
other names	N -acetyl-4-aminophenol N -acetyl- p -aminophenol 4-acetaminophenol Acetaminophen ( USAN ) APAP 4'-hydroxyacetanilide p -hydroxyacetanilide N - (4-hydroxyphenyl) acetamide ( IUPAC ) Paracetamolum ( Latin ) med. Abbreviation : PCM
Molecular formula	C 8 H 9 NO 2
Brief description	white, odorless, monoclinic prisms
External identifiers / databases
CAS number 103-90-2 EC number 203-157-5 ECHA InfoCard 100.002.870 PubChem 1983 DrugBank DB00316 Wikidata Q57055
Drug information
ATC code	N02 BE01
Drug class	Non-opioid analgesic Antipyretic
Mechanism of action	Inhibition of cyclooxygenase-2 (COX-2) in the spinal cord
properties
Molar mass	151.16 g · mol -1
density	1.29 g cm −3 (21 ° C)
Melting point	169  ° C ( polymorphic form I) 159 ° C (polymorphic form II)
pK s value	9.38
solubility	little in water (14 g l −1 at 20 ° C) soluble in ethanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302-315-317-319 P: 260-273
MAK	10 mg m −3
Toxicological data	1944 mg kg −1 ( LD 50 ,  rat ,  oral ) 338 mg kg −1 ( LD 50 ,  mouse ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Paracetamol is an analgesic and antipyretic drug from the group of non-opioid analgesics . In North America and Iran, the common name for the substance is acetaminophen .

The name paracetamol is derived from the chemical name par a - ( acet yl am ino) phen ol (or para - ( acet yl amino ) phen ol). The substance is a derivative of both acetic acid and the aminophenol p-hydroxyaniline. Paracetamol is used in self-medication as a single preparation or as part of various combination preparations for the symptomatic treatment of cold symptoms and pain . Since their introduction in the 1950s, almost 70 years after Harmon Northrop Morse first manufactured this active ingredient , medicines containing paracetamol - alongside those containing acetylsalicylic acid and ibuprofen - have been among the most widely used pain relievers worldwide. Paracetamol has been on the WHO list of essential drugs since 1977 .

history

The production of paracetamol as a product of the reduction of p - nitrophenol with zinc in glacial acetic acid (concentrated acetic acid) was first described in 1878 by Harmon Northrop Morse . Josef von Mering used paracetamol for the first time in medicine in 1887, but its use caused little stir. In the following years, two substances closely related to paracetamol, acetanilide and phenacetin , gained significantly more therapeutic importance .

Paracetamol was first detected in the urine of a person who had taken phenacetin in 1893. In 1899, paracetamol was also recognized as a metabolite ( metabolite ) of acetanilide - these discoveries, however, remained without resonance, so that paracetamol was still not used in medicine.

Julius Axelrod 1973

Paracetamol only became better known after the Second World War , when it was identified a second time as a metabolite of phenacetin by Bernard B. Brodie and Julius Axelrod at the New York City Department of Health in 1948 . On behalf of the government, they researched new painkillers and showed in their work that the pain-relieving effect of acetanilide and phenacetine is entirely due to the breakdown product of these substances, paracetamol. They suggested using this substance in its pure form in order to avoid the toxic side effects of the original substances .

Paracetamol was first used in a finished drug in 1955 in the USA in Tylenol Children's Elixir from McNeil Laboratories. Paracetamol has been available in tablet form with 500 mg of active ingredient since 1956 and was sold in Great Britain under the brand name Panadol , manufactured by Frederick Stearns & Co, an offshoot of Sterling Drug Inc. It was only available on prescription and was advertised as a pain reliever and fever lowering agent, which was also easy on the stomach. Acetylsalicylic acid, which was already known at the time, is less stomach-friendly. In 1958, a children's version of the preparation called Panadol Elixir came onto the market. In 1959, paracetamol was launched on the German market by the Munich company bene-Arzneimittel as the first monopreparation under the brand name ben-u-ron .

Paracetamol has been monographed in the British Pharmacopoeia , the " British Pharmacopoeia ", since 1963 . Shortly afterwards it was also included in the pharmacopoeias of other European countries.

In 1982 there was a case of product sabotage in the USA , the consequences of which prompted the responsible state authority, Food and Drug Administration , to issue stricter protective regulations. Seven patients died from poisoned paracetamol preparations. Preparations with a market value of 100 million US dollars were recalled.

After hamster purchases occurred during the COVID-19 pandemic in Germany , the amount sold in Germany was limited to one pack per patient in April 2020.

application

Application areas (indications)

Paracetamol is approved as a finished drug for the treatment of mild to moderate pain and fever. Using it is used mainly for mild headache , slight toothache , menstrual pain , sunburn and arthritis-related joint pain as well as migraine .

Paracetamol in a fixed combination with caffeine (400 mg paracetamol, 50 mg caffeine) is also approved for the treatment of mild to moderate pain . This combination is said to be 1.3 to 1.7 times more potent than paracetamol alone and enables the paracetamol dose to be reduced. Caffeine also shortens the time it takes for paracetamol to take effect. The triple combination of paracetamol with acetylsalicylic acid and caffeine also leads to increased effectiveness and is therefore recommended by the German Migraine and Headache Society as the first choice for the treatment of migraines and tension headaches .

In a fixed combination with codeine (co-codamol) or tramadol , paracetamol is approved for the treatment of moderately severe to severe pain.

Since colds can be accompanied by fever, pain in the limbs and headaches, paracetamol is approved in combination with other drugs such as antihistamines , cough suppressants , cough suppressants or vitamin C as an analgesic and antipyretic component of many so-called "flu remedies" or "cold remedies".

Contraindications (contraindications) and warnings

Paracetamol must not be used if there is a known hypersensitivity to paracetamol or if there is severe impairment of liver function due to liver failure with a Child-Pugh score of 9 or higher. In patients with liver failure with a Child-Pugh score of <9, Gilbert-Meulengracht syndrome , chronic kidney failure with a creatinine clearance of less than 10 ml / min or chronic alcohol abuse , paracetamol may only be used with special care under medical supervision and if necessary an adjusted dosage.

Long-term, high-dose, improper use of paracetamol can result in drug-induced headache . Headache and accompanying symptoms worsen after abrupt discontinuation.

pregnancy and breast feeding period

Mostly older reproduction studies and epidemiological data gave no indication of a harmful effect of paracetamol on the health of the fetus or the newborn. Numerous studies suggest a possible connection between the use of paracetamol during pregnancy and an increased incidence of asthma in children. The influence of paracetamol on haematopoietic stem cell development in the umbilical cord blood is discussed as a possible pathomechanism, which can lead to a differentiation of immune cells. For long-term use during pregnancy, there are insufficient data to assess the safety. However, a current study by the University of Oslo clearly suggests that taking paracetamol during pregnancy and breastfeeding, especially over a longer period of time, can lead to a later developmental delay in the unborn child. Over a period of nine years, over 48,000 children, including almost 3,000 pairs of siblings, were examined.

The suspicion that children who were exposed to the active ingredient paracetamol in the womb can later become behaviorally abnormal was confirmed by a study by researchers at the University of Bristol with a total of 14,500 mothers and their children. In seven-year-old children whose mothers had taken paracetamol between the 19th and 32nd week of pregnancy, the risk of behavioral problems increased by 46 percent.

Researchers at the Icahn School of Medicine at Mount Sinai reported in January 2018 that paracetamol use during pregnancy was linked to an increased rate of speech delay in girls. In an initial study of this type, researchers found an increased rate of speech delay in girls 30 months old who were born to mothers who frequently used acetaminophen in early pregnancy. These results are consistent with studies reporting decreased IQ and increased communication problems in children born to mothers who used more acetaminophen during pregnancy. Looking at language development is important because it has been shown to be predictive of other neurodevelopmental disorders in children. The Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy Study (SELMA) provided data for this research. Information was collected from 754 women enrolled in the study between weeks 8-13 of their pregnancy.

Although small amounts of paracetamol are excreted in breast milk, no undesirable effects on the infant have been reported when taking paracetamol while breastfeeding.

Method of application and dosage

Paracetamol can be administered orally , rectally, or intravenously . Paracetamol is dosed depending on age and body weight. For oral use, 10 to 15 mg of paracetamol per kg of body weight are generally used as a single dose (for example 1000 mg three times a day) and up to 60 mg / kg of body weight as the total daily dose. For adults (from 43 kg) this corresponds to a maximum daily dose of around 4000 mg divided into three to four individual doses. Dose adjustments are made in patients with impaired kidney or liver function.

Interactions

Probenecid inhibits the glucuronidation of paracetamol and thus its excretion. An inhibition of the excretion of paracetamol can also be observed after concomitant intake of salicylamide . Alcohol and drugs, as inducers of cytochrome P450 enzyme system function, such as carbamazepine and barbiturates , lead to an increased formation of liver harmful metabolic products ( metabolites ) of paracetamol. Ion exchangers such as cholestyramine reduce the absorption of paracetamol. The onset of the effect of paracetamol can be slowed down or accelerated by drugs that affect gastrointestinal activity, such as metoclopramide .

Paracetamol itself only rarely affects the effect of other drugs. When taken regularly, paracetamol increases the effects of anticoagulants such as phenprocoumon and warfarin . The side effects of zidovudine , which damage the blood count, can also be increased if paracetamol is taken at the same time. Furthermore, there has been increasing evidence recently that paracetamol and certain other pain relievers from the group of non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs (NSAIDs) , such as. B. acetylsalicylic acid (aspirin), can make vaccines less effective by the body making fewer of the protective antibodies after vaccination . The latter is attributed to the fact that drugs such as paracetamol impair the terminal differentiation of B cells into antibody-producing plasma cells . Researchers and doctors therefore advise avoiding appropriate medication for some time before and after vaccination.

Side effects

Paracetamol only rarely or very rarely shows undesirable effects when used as intended . None of the side effects related to acetaminophen are more common than 1 in 1,000 patients. These include an increase in certain liver enzymes ( transaminases ) in the serum (frequency: 0.01–0.1%). Very rarely (frequency: <0.01%) or in isolated cases serious changes in the blood count such as thrombocytopenia (reduced number of blood platelets) and agranulocytosis could be observed. Just as rarely, allergic reactions in the form of a simple skin rash or hives up to a shock reaction can occur. Also with a frequency of less than 0.01% there was a spasm of the respiratory muscles in sensitive persons ( analgesic asthma ). If paracetamol is used as directed, the risk of analgesic nephropathy is very low. Whether this risk is increased by combined use with acetylsalicylic acid and caffeine is a matter of controversy.

Epidemiological studies link paracetamol consumption in childhood, depending on the dose, with a long-term increased risk of asthma and an increased risk of inflammation of the nasal mucosa and the conjunctiva ( allergic rhinitis ) and skin inflammation ( eczema ). Other studies contradict the thesis that paracetamol promotes asthma.

The breakdown of paracetamol consumes glutathione and can lead to a deficiency of sulfur-containing amino acids in older patients, which in the long term can generally lead to cardiovascular susceptibility (susceptibility of the blood circulation) via the glutathione deficiency.

Long-term use of paracetamol is suspected to increase the risk of a number of blood cancers.

In view of the severe and life-threatening skin reactions observed in recent years with the use of paracetamol, the FDA advises users to consult their doctor if they develop skin reactions and to discontinue use of the preparation. A corresponding warning is to be printed on the drug packs of preparations containing paracetamol in the USA.

The Pharmacovigilance Committee for Risk Assessment (PRAC) of the European Medicines Agency (EMA) recommended in September 2017 that extended-release paracetamol products be withdrawn from the market. The risk of an overdose outweighs the advantage of a longer-acting preparation. A final decision by the EMA is still pending. The manufacturers concerned still have the opportunity to request a further review by the PRAC.

New studies suggest that acetaminophen affects compassion and empathy. It seems to decrease the ability to empathize with the sensation of pain.

Harmful use and overdose

Paracetamol overdoses as a result of ignorance of the maximum daily dose, non-observance of contraindications and restrictions on use as well as self-damaging, mostly suicidal intent are often associated with severe impairment of liver function. An overdose of more than 150 milligrams per kilogram of body weight, equivalent to 10 grams for adults, can lead to irreversible damage to the liver cells or even to liver failure . Alcoholics or patients with a reduced excretion of paracetamol can suffer liver damage even with a significantly lower dose. In England and Wales , around 30,000 patients per year are hospitalized with paracetamol poisoning as a result of suicidal intent, of whom around 150 succumb to poisoning. A restriction in the size of paracetamol preparations in the UK only showed a reduction in suicides after a few years. As in the UK, paracetamol is the most common cause of acute liver failure in the US, with around half of all intoxications occurring unintentionally. In 2011, the US FDA asked the manufacturers of drugs in which paracetamol is combined with an opioid to limit the paracetamol dose to 325 mg per dosage unit in order to reduce the risk of toxic effects on the liver. The FDA also wants to develop measures for OTC drugs .

The first symptoms of acute acetaminophen poisoning, which occur within the first 48 hours and peak after about four to six days, are nausea, vomiting, loss of appetite, paleness and persistent abdominal pain as signs of liver damage. At the same time, clinical values ​​such as liver transaminases , lactate dehydrogenase , bilirubin values and prothrombin time can be increased. If no prompt treatment is followed, around 10% of patients with acute acetaminophen poisoning will suffer permanent, severe liver damage. In turn, around 10 to 20% of these patients die as a result of liver failure. Acute kidney failure occurs less frequently. In one study, nephropathy was observed in patients with previous renal impairment who took naproxen and paracetamol at the same time (cumulative 0.4 and 1.0 kg over years). This indicates a combined negative effect of naproxen and paracetamol. Other liver-independent symptoms observed after acetaminophen poisoning are heart muscle abnormalities and pancreatitis .

The cause of the liver toxicity of paracetamol is its metabolite N- acetyl- p -benzoquinone imine (NAPQI). The formation of this liver-damaging metabolite is increased by regular consumption of alcohol and drugs with an enzyme-inducing effect, such as carbamazepine. A suitable antidote for paracetamol poisoning is N -acetylcysteine , which scavenges toxic paracetamol metabolites, such as N -acetyl- p -benzoquinonimide, with the formation of non-toxic conjugates. This can prevent progression to irreversible liver damage or liver failure, provided the antidote is administered in good time. N -acetylcysteine ​​is considered effective if given within ten hours. Various treatment regimens recommend the use of about 150 mg / kg body weight as a single dose and a total dose of 300 to 1330 mg / kg body weight divided over 20 to 68 hours. For this purpose, N-acetylcysteine ​​is available for intravenous administration as well as for oral use ( effervescent tablets ). Activated charcoal can also be used immediately for up to about an hour after an overdose of paracetamol . In the case of advanced acute liver failure, liver transplantation is the only remaining treatment option that gives the patient a chance of survival.

Application in veterinary medicine

Because of its potentially damaging effects on the liver, paracetamol should be used with caution in veterinary medicine. In cats and young animals, the administration of paracetamol very quickly leads to poisoning with methaemoglobin formation , anemia , hemoglobinuria , liver damage, jaundice , dyspnoea and palpitations , as these can only insufficiently glucuronide the active ingredient . Dogs tolerate the active ingredient well, but the duration of action is very short (about two hours), so that the active ingredient is practically useless. The use of paracetamol in pigs is permitted among farm animals, whereby a residue limit is not necessary (Appendix II of Regulation 2377/90 ). Even the smallest amounts of paracetamol are said to have a lethal effect on snakes.

pharmacology

Mode of action (pharmacodynamics)

In contrast to the pain relievers acetylsalicylic acid or ibuprofen , paracetamol has an anti-inflammatory effect that can only be determined under laboratory conditions and is accordingly not included in the group of classic " non-steroidal anti-inflammatory drugs " (also: non-steroidal anti-inflammatory drugs, NSAIDs ; English non-steroidal anti-inflammatory drugs, NSAID ). In contrast to the classic NSAIDs, paracetamol has hardly any effect on the peripheral cyclooxygenase . For this reason, the side effects (including gastrointestinal ulcers) are much less pronounced. Paracetamol also has practically no influence on the aggregation of the blood platelets and therefore no anti-coagulant effect like acetylsalicylic acid.

The exact mechanism of action of paracetamol is still unknown. It is known that several controversially discussed mechanisms interact and that the pain-relieving effect occurs to a not inconsiderable extent in the brain and spinal cord .

Inhibition of cyclooxygenases

Based on the discoveries of John Vanes, it was long assumed that the analgesic effect of paracetamol is due to the cyclooxygenases , the enzymes involved in inflammatory reactions and the development of pain. The cyclooxygenase enzymes play a key role in the transmission of pain to the brain through the formation of pain and inflammation mediators from the group of prostaglandins . An inhibition of cyclooxygenases could explain the comparable analgesic potency of paracetamol and acidic non-opioid analgesics such as acetylsalicylic acid and ibuprofen, but not the largely lacking anti-inflammatory effectiveness and the equally largely missing gastrointestinal side effects of paracetamol. The reason for these differences was assumed to be a different distribution of paracetamol and acidic non-opioid analgesics in body tissue, whereby paracetamol is evenly distributed in the body and acidic non-opioid analgesics accumulate in the sense of drug targeting, for example in the stomach and in the inflamed tissue. Another possible explanation was found with the discovery of the cyclooxygenase isoenzyme COX-3 , a variant of COX-1 that occurs in particular in the cerebral cortex . However, this thesis was rejected a few years later because the COX-3 is actually just another splice variant of the COX-1 and is not sufficiently expressed to produce a biological effect. According to recent studies, a weakly suppressing effect on the cyclooxygenase isoenzyme COX-1 and a strong one on COX-2 in vivo are responsible for the effects of paracetamol. This matches its weak effect on platelets (blood platelets).

Interactions with the serotonin system

Further experimental data suggest that paracetamol mediates its effects by activating serotoninergic pain-relieving mechanisms. In particular, serotonin receptors of the 5-HT _{3 type} should play an important role. The pain-relieving effect is attributed to a projection of serotoninergic neurons into the spinal cord. This hypothesis about the mechanism of paracetamol shows analogies to the mode of action of opioids such as morphine . Alternatively, an analgesic serotoninergic effect of paracetamol can also be interpreted as a consequence of the inhibition of prostaglandin function, since most serotoninergic neurons also express prostanoid receptors.

Interactions with the endocannabinoid system

Structure of the paracetamol metabolite N -arachidonoylphenolamine

An interaction of paracetamol with the body's own cannabinoid system ( endocannabinoid system ) was suspected due to a weak euphoric , relaxing and calming effect of aniline-type analgesics in addition to the analgesic effect . Indeed, an interaction of paracetamol with the endocannabinoid system has been demonstrated in vivo . A metabolite of paracetamol, N- arachidonoylphenolamine , which is especially formed in the brain, has an antipyretic and analgesic effect via an indirect effect on cannabinoid receptors. N -Arachidonoylphenolamine interacts with the vanilloid receptor TRPV1, which occurs on many free nerve endings that function as nociceptors and is also involved in the regulation of body temperature. In addition, this paracetamol metabolite inhibits the cellular re- uptake of anandamide and thus leads to an increase in the concentration of this endogenous cannabinoid .

Other mechanisms of action

In addition to an interaction of paracetamol with cyclooxygenases, the serotonin system and the endocannabinoid system, an inhibiting influence of paracetamol on hyperalgesia caused by glutamate or substance P is discussed as the cause of its analgesic effect. Paracetamol is also involved in inhibiting the release of the messenger substance nitrogen monoxide (NO).

In addition, there are indications that paracetamol is not only able to alleviate physical pain, but also psychological suffering caused by social exclusion or rejection (so-called social pain ). According to the authors, this is an indication that there is a substantial overlap between physical and psychological pain with regard to the affected brain regions.

Pharmacokinetics

Main metabolic routes of paracetamol

The maximum effective concentration of paracetamol is reached after about 30 to 60 minutes after oral administration. With rectal use, which achieves a bioavailability of 68 to 88%, maximum plasma concentrations are reached after approximately 3 to 4 hours. The plasma half-life is 1 to 4 hours. In premature babies it can be significantly higher due to a not yet fully developed metabolic system.

Structural formula of N -acetyl- p -benzoquinone imine (NAPQI)

The decomposition of paracetamol is carried out mainly in the liver , where the majority of the substance as part of a Phase II reaction by combining with sulfate or glucuronic inactivated ( glucuronidation ) and then via the kidney is excreted.

The toxic effect can be traced back to a product that is produced in small quantities, which is produced in particular via the breakdown via the cytochrome P450 enzyme system , N- acetyl- p -benzoquinone imine . The cytochrome P450 isoenzyme CYP 2E1 , but also CYP 1A2 and CYP 3A4 , are particularly involved in the formation of this very reactive metabolite . Normally, N- acetyl- p -benzoquinone imine is immediately captured by the reaction with glutathione (GSH) and the resulting product is excreted via the kidneys. However, glutathione is only available to a limited extent in the liver and its replication cannot be increased sufficiently. Therefore, the glutathione portion is exhausted in the event of an acute paracetamol overdose. The N- acetyl- p -benzoquinone imine now reacts with structural and functional proteins of the liver cells , which can lead to liver cell necrosis and clinical liver failure. Chronic alcohol consumption and enzyme-inducing drugs increase the metabolism of paracetamol via the cytochrome P450 enzyme system to N -acetyl- p -benzoquinone imine and thus increase the toxicity of paracetamol.

An alternative route of degradation of paracetamol involving the cytochrome P450 isoenzymes CYP 2A6 and CYP 2B1 leads to 3-hydroxyparacetamol. This metabolite, which is excreted after glucuronidation, shows a significantly lower toxicity than N- acetyl- p -benzoquinone imine.

chemistry

structure

Paracetamol is a derivative of para - aminophenol , i.e. a phenol ( N -acetyl- p -aminophenol) and a derivative of aniline ( p -hydroxyacetanilide) at the same time . Paracetamol can also be understood as acetamide , i.e. as the amide of acetic acid , from which the name N - (4-hydroxyphenyl) acetamide, assigned according to IUPAC regulations, results.

Due to the aniline structure it contains, paracetamol as well as acetanilide , phenacetin and propacetamol belong to the analgesic group of aniline derivatives. Acetanilide, phenacetin and propacetamol can be viewed as precursors ( prodrugs ) that are converted to paracetamol in the organism.

Acetanilide	Paracetamol	Phenacetin	Propacetamol

Pure paracetamol on a porcelain surface

Substance properties

Paracetamol is a white, crystalline solid that occurs in at least two different modifications. This polymorphism is of pharmaceutical importance and has an impact on the compressibility of the drug. Orthorhombic paracetamol shows a compressibility that is superior to the thermodynamically more stable monoclinic modification. Paracetamol is readily soluble in alcohols in both modifications , but only moderately in cold water (14 g / l at 25 ° C), but it is in boiling water. Paracetamol has a density of 1.293 grams per cubic centimeter. As a phenol, it is slightly acidic. The pH of a saturated, aqueous solution is around six. Paracetamol has a characteristic, slightly bitter taste .

Manufacturing

Classic production of paracetamol

Various synthetic routes have been described for the production of paracetamol. The classic process uses the N -acetylation of p - aminophenol . This raw material can be produced by nitration and subsequent reduction of phenol or alternatively starting from aniline or p - chlorophenol . To acetylate the aminophenol, it is allowed to react with excess acetic anhydride, the end product as well as N , O -diacetylated by-product being formed with elimination of acetic acid . The latter hydrolyses in an aqueous medium or in a weakly alkalized medium due to the higher hydrolysis sensitivity of the esters - compared to the amide bond, selectively to paracetamol.

One process of industrial large-scale production starts with phenol and comprises three steps. Phenol is acetylated with acetic anhydride in the presence of hydrofluoric acid in the para position to form p -hydroxyacetophenone . Alternatively, p- hydroxyacetophenone can also be obtained from phenyl acetate at low temperature and with aluminum chloride as the Lewis acid ( Fries rearrangement ). The p -hydroxyacetophenone is then condensed with hydroxylamine to form the oxime . This rearranges in the presence of thionyl chloride according to Beckmann to paracetamol.

A more recent variant is the reducing amidation of p -nitrophenol with thioacetic acid .

Analytics

Cerimetric determination of the paracetamol content

According to the European Pharmacopoeia , paracetamol can be identified with the help of chemical and instrumental analytical methods. Paracetamol can be detected by oxidation with potassium dichromate with the formation of a blue dye. The acetyl group can be detected after hydrolysis with the help of lanthanum nitrate and iodine . Alternatively, paracetamol can be detected by a positive marquis reaction after hydrolysis with the help of formaldehyde . The hydrolysis product also gives positive evidence for primary aromatic amines. The phenolic structure can also be identified with iron (III) chloride , which forms a blue, acid-labile complex.

The content of paracetamol is determined according to the European Pharmacopoeia after hydrolytic cleavage of paracetamol to p- aminophenol in the classic way as oxidimetric titration with the help of cerimetry . Alternative methods of determination of levels include instrumental methods such as HPLC . For the quantitative determination of paracetamol in urine, blood plasma or serum, colorimetric assays and immunassays are available in addition to HPLC and gas chromatography methods.

Given its frequent use, paracetamol can now also be detected in rivers in addition to ibuprofen .

Commercial preparations

Economic data, tax regulation

Paracetamol is one of the best-selling drugs worldwide. The monopreparation Paracetamol-ratiopharm was the second most frequently purchased drug in Germany with over 20 million packaging units in 2008. The combination preparation Thomapyrin (12.4 million packaging units in 2008) can also be found in the top 10 of the best-selling drugs. The total annual turnover of paracetamol in Germany is estimated at around 31 million packs with a market value of around 60 million euros.

Paracetamol preparations for oral administration for the treatment of mild to moderately severe pain and / or fever in a total amount of active ingredients of up to 10 g per package and for rectal use are not subject to prescription in Germany . Oral quantities of more than 10 g were made subject to the prescription requirement in April 2009 with the aim of reducing the frequency of paracetamol poisoning caused by improper use. Similar restrictions in the UK resulted in a small decrease in paracetamol-related deaths. An application for a general prescription requirement for paracetamol in Germany was rejected in 2012. In Germany, paracetamol is only available in rapid-release dosage forms - for countries such as Belgium, Denmark, Finland, Luxembourg, Portugal, Romania and Sweden, where sustained-release versions are also available, the Pharmacovigilance Committee of the European Medicines Agency confirmed its recommendation in December 2017, to suspend the approval of these dosage forms, the coordination group of the association of national approval authorities agreed.

A prescription is required for paracetamol-containing infusion solutions or for use in veterinary medicine, as well as for oral combination preparations with prescription substances such as codeine , metoclopramide and tramadol .

Monopreparations

Acetalgin (CH), ben-u-ron (D, A, CH), Captin (D), Contac (D), Contra-Pain P (CH), Dafalgan (CH), Dolprone (CH), Enelfa Dr. Henk (D), GRIPPEX (D), Mexalen (A), Panadol (CH), Parapaed (D), Perfalgan (A, D, CH), RubieMol (A), Tylenol (USA, CH) as well as numerous generics.

Combination preparations

• with acetylsalicylic acid : Fibrex (D), Thomapyrin 300 mg / 200 mg (D, A)
• with butylscopolamine : Buscopan Plus (A, D)
• with caffeine : Azure (D), COPYRKAL (D), Neopyrin (D), Octadon (D), Panadol Extra (CH), Prontopyrin (D), Vivimed (D)
• with codeine : Contraneural (D), Gelonida (D), Nedolon (D), Optipyrin (D), Paracetamol comp. STADA (D), talvosilen (D), Titretta (D), Co – Dafalgan (CH)
• with diphenhydramine : Panadol PM (USA)
• with metoclopramide : Migraeflux MCP (D), Migraine-Neuridal (D), Migräneerton (D), Migralave + MCP (D)
• with phenylephrine : Doregrippin (D)
• with Tramadol : DOLEVAR (D), Zaldiar (CH, D)
• with ascorbic acid (vitamin C): Mexa-Vit C (A)

Multiple combinations:

• with acetylsalicylic acid and caffeine: Chephapyrin (D), dolomo (D), Dolopyrin (D), HA tablets N (D), Melabon (D), Neuralgin (D), Novo Petrin (D), ratiopyrin (D), Thomapyrin CLASSIC (D), Thomapyrin INTENSIV (D), TITRALGAN (D), Thomapyrin (A), InfluASS (A), Irocophan (A)
• with ascorbic acid, caffeine and chlorphenamine : Grippostad (D)
• with caffeine and codeine: Azur compositum (D)
• with acetylsalicylic acid and ascorbic acid: Grippal + C (D)
• with guaifenesin , phenylephrine and ascorbic acid: WICK DayMed cold drink for the day (D)
• with phenylpropanolamine and dextromethorphan : Basoplex cold capsules (D), WICK DayMed cold capsules (D)
• with doxylamine , ephedrine , dextromethorphan: WICK MediNait cold syrup (D)
• with doxylamine and dextromethorphan: WICK MediNait cold syrup with honey and chamomile aroma (D, CH)
• with phenylephrine and dextromethorphan: Contac Cold Trunk Forte (D)
• with pheniramine , phenylephrine, ascorbic acid: NeoCitran (A, CH)

literature

• A. Bertolini, A. Ferrari, A. Ottani, S. Guerzoni, R. Tacchi, S. Leone: Paracetamol: new vistas of an old drug . In: CNS Drug Reviews . tape 12 , no. 3–4 , 2006, pp. 250–275 , doi : 10.1111 / j.1527-3458.2006.00250.x , PMID 17227290 .
• Ernst Mutschler u. a .: Mutschler - drug effects textbook of pharmacology and toxicology . 9th edition. Scientific Verlagsgesellschaft, Stuttgart 2008, ISBN 978-3-8047-1952-1 .
• RE Brandlistuen, E. Ystrom, I. Nulman, G. Koren, H. Nordeng: Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study . In: International Journal of Epidemiology . tape 42 , no. 6 , January 10, 2014, p. 1702-1713 , doi : 10.1093 / ije / dyt183 .

Web links

Commons : Paracetamol  - Collection of images, videos and audio files

• Paracetamol supplements. Swiss Medicines Compendium
• Superbrands: Panadol . (PDF; English)
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Individual evidence

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