Acetylsalicylic acid

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of acetylsalicylic acid
General
Surname Acetylsalicylic acid
other names
  • 2- (acetyloxy) benzoic acid ( IUPAC )
  • Salicyl acetate
  • Acetic salicylic acid
  • Acetalicylic acid
  • o -acetoxybenzoic acid
  • ASS
  • Aspirin ( USP , BP , JP )
Molecular formula C 9 H 8 O 4
External identifiers / databases
CAS number 50-78-2
EC number 200-064-1
ECHA InfoCard 100,000,059
PubChem 2244
DrugBank DB00945
Wikidata Q18216
Drug information
ATC code
Drug class
Mechanism of action

irreversible cyclooxygenase - inhibitor

properties
Molar mass 180.16 g mol −1
Physical state

firmly

density

1.35 g cm −3 (20 ° C )

Melting point

136 ° C (partly decomp.)

boiling point

decomposes

pK s value

3.49

solubility
  • slightly soluble in water (2.5 g l −1 at 15 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302
P: 301 + 312 + 330
MAK

Switzerland: 5 mg m −3

Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Acetylsalicylic acid ( ASA for short ) is a widely used pain reliever , anti-inflammatory , antipyretic and platelet aggregation inhibitor (TAH) drug from the group of nonsteroidal anti-inflammatory drugs (NSAIDs). ASA has been on the WHO Essential Medicines List since 1977 . The substance has been sold in various products by pharmaceutical manufacturers since the beginning of the 20th century.

The name aspirin , which initially became a synonym for ASA in English-speaking countries and later also internationally, is a brand name of Bayer AG for drugs with this active ingredient.

nomenclature

Acetylsalicylic acid is the common name for 2-acetoxybenzoic acid, as it is called according to the IUPAC regulations. It is a derivative of salicylic acid ( o -hydroxybenzoic acid ), which means that acetylsalicylic acid can be understood both as a derivative of benzoic acid (see IUPAC name) and as an ester of acetic acid (acetic acid salicyl ester).

etymology

Pure acetylsalicylic acid was first produced in 1897 by Felix Hoffmann in collaboration with Arthur Eichengrün in the paint factories. Friedr. Bayer & Co. synthesized. The brand name Aspirin was added to the trademark role of the Imperial Patent Office on March 6, 1899 . This name is derived from the real meadowsweet , a salicylate rose plant that was also called spar (outdated: Spiraea ulmaria L. today: Filipendula ulmaria (L.) Maxim.): 'A' (for the acetyl group), 'spir' is supposed to refer to the history of the active ingredient (based on spiric acid , which is chemically identical to salicylic acid) and 'in' as a common suffix of the chemical naming of that time. The name was coined by Kurt Witthauer , senior physician at the deaconess hospital in Halle / Saale , who published the first clinical study on the use of acetylsalicylic acid in April 1899.

Trade names and dosage forms

Acetylsalicylic acid is used as a monopreparation worldwide in over 500 finished drug in the dosage form of tablets , sublingual tablets , film-coated tablets , orodispersible tablets , drinking tablets , powders, granules , chewable tablets , chewable coated tablets , effervescent tablets , prolonged release tablets , capsules , prolonged-release capsules, injection solutions , suppositories and dragees marketed. Below are some examples of trade names :

  • Germany: ASS-AbZ, Acesal, Acetylin (hist.), Alka-Seltzer, Aspirin, Aspirin iv (formerly Aspisol), Eudorlin, Godamed, Herz-ASS, Miniasal, Togal-ASS, ASS-ratiopharm
  • Switzerland: Alcacyl, Asa-Tabs, Aspégic, Aspirin, Aspirin Direkt, Aspirin Effect, Aspirin Migraine, Aspirin protect, Aspro, Contra-Pain plus, Kardégic, Tiatral
  • Austria: Acekapton, Aspirin, Aspro Classic, Herz-ASS, Thrombo-ASS, Togal Mono, ASS Genericon

In addition to these monopreparations , there are also numerous generics and combination preparations on the market which, in addition to acetylsalicylic acid, also contain vitamin C , paracetamol , caffeine or pseudoephedrine hydrochloride, such as Aspirin Plus C, Aspirin Plus C Forte - with the active ingredients acetylsalicylic acid and ascorbic acid (vitamin C); Aspirin Caffeine - with the active ingredients acetylsalicylic acid and caffeine or Aspirin Complex - with the active ingredients acetylsalicylic acid and pseudoephedrine hydrochloride.

The abbreviation Asa (or ASA , instead of ASS) shown above comes from the English acetylsalicylic acid .

history

White willow ( Salix alba )

Willow bark was used as a remedy for fever and pain of all kinds at the latest in the early advanced civilizations . Hippocrates of Kos , Dioscurides and the Roman scholar Pliny the Elder saw the willow bark as a medicine . By boiling willow tree bark , Germanic peoples and Celts obtained and used for medicinal purposes extracts that contained substances related to synthetic acetylsalicylic acid. In 1763, the reported in Oxford living clergyman Edward Stone of the Royal Society in London that these known from the tradition findings were correct. 1828 succeeded Johann Andreas Buchner , the salicin , a chemical relative of the ASS, which in the body to salicylic acid from said willow bark extracts (is reacted, willow , Salix to isolate sp.), As well as the French chemist Pierre-Joseph Leroux .

Also castoreum (beaver), a secretion of the anal gland of the beaver , contains salicylic acid and was until the 19th century against spasms, hysterical seizures, nervousness u. v. m. used. In Graeco-Roman antiquity, the substance was already known as an active ingredient against epilepsy .

The precursor salicylic acid (the world's first industrially manufactured and “packaged” drug) was produced on an industrial scale from 1874 by Friedrich von Heyden ( Chemische Fabrik von Heyden in Radebeul ) using the Kolbe-Schmitt reaction . However, the bitter taste of the substance and side effects such as stomach upset severely restricted its use as a drug .

The chemist Charles Frédéric Gerhardt had already synthesized acetylsalicylic acid in non-pure form in Strasbourg in 1853 . By boiling acetyl chloride with salicylic acid, Hugo von Gilm (1831–1906) was able to obtain impure o- acetylsalicylic acid as a water-insoluble solid in 1859 . The methods of Friedrich von Heyden and Hugo von Gilm were examined in detail by Karl Kraut in 1869 , and anhydrides and “acetylosalicylic acid” (melting point 118 ° C) which were difficult to characterize were formed in both of them in very different proportions.

In 1872, Hugo Schiff demonstrated that acetyl-containing anhydrides of salicylic acid are thermally very easily converted into isomeric salicylic acid esters and that higher condensation products are also formed. From acetyl chloride and salicylic acid, but with the addition of iron (III) chloride under Friedel-Crafts conditions from 1877 , p -acetylsalicylic acid (melting point 210 ° C.) was produced in early 1897 .

Kurt Witthauer: Aspirin, a New Salicylic Preparation (April 1899)

On August 10, 1897, Bayer's main plant in Wuppertal-Elberfeld was the first to synthesize o- acetylsalicylic acid (melting point 136 ° C) from acetic anhydride and salicylic acid , free of byproducts. In a US patent from August 1, 1898, the inventor Felix Hoffmann once again made it clear in detail that only with his method and in contrast to the variants described by Kraut, the desired acetylsalicylic acid is formed in pure form. The patent was granted in the USA and Great Britain, but not in Germany, as Chemische Fabrik v. Heyden in Radebeul near Dresden under the chemist Carl Kolbe has been producing and selling acetylsalicylic acid on an industrial scale since 1897, first under its chemical name and later under the trade name Acetylin .

The substance was tested by Kurt Witthauer at the Diakoniekrankenhaus in Halle in 1898 for its benefits on over 50 patients and he particularly emphasized the good tolerance in comparison with other salicylic preparations. A description of the industrial sulfuric acid-catalyzed process can be found in Ullmann's Enzyclopadie from 1915. On April 7, 1921, Bayer applied for a patent for a modification of this process. Instead of sulfuric acid, a small addition of pyridine was also suitable as a catalyst under otherwise milder reaction conditions.

In 1949 Arthur Eichengrün published a paper in which he wrote that he had planned and coordinated the development of aspirin and some of the necessary auxiliary substances. Already before that, Eichengrün wrote from the concentration camp - almost half a century after the invention of aspirin - to IG Farben (Bayer), when he saw himself near his death, that Hoffmann was only involved in the invention of aspirin in the way that he (in the first chemically completely pure synthesis of acetylsalicylic acid) followed Eichengrün's instructions without even knowing what he was doing. During National Socialism , he was still denied as a participant or even an inventor, as was usual with all Jewish achievements, and the invention of aspirin was publicly awarded primarily to Hoffmann. Eichengrün read this himself, after his dismissal, in an exhibition from the time of National Socialism - on the gate of which "Jews are prohibited from entering" was emblazoned - on a blackboard on the subject of aspirin. On it Hoffmann and a person unrelated to the development of aspirin were named as inventors, without any mention of Eichengrün. In many historical treatises and encyclopedias on the subject, due to these processes during National Socialism and the history books that were influenced by it, Felix Hoffmann is primarily named as the inventor or probable inventor, and Eichengrün's declaration in his work published in 1949 is often only referred to as an assertion.

Both Felix Hoffmann and Arthur Eichengrün are discussed as inventors of the by-product-free synthesis route of acetylsalicylic acid. Most recently, in 1999, Walter Sneader from the Department of Pharmaceutical Sciences at Strathclyde University in Glasgow came to the conclusion that Eichengrün was the inventor of aspirin - Bayer immediately denied this theory in a press release. Eichengrün was increasingly hindered in his scientific work due to his Jewish origins during the Nazi era. What is certain is that Eichengrün was promoted to head of the pharmaceutical department at Bayer AG after aspirin was approved, and Hoffmann became head of the marketing department. However, Bayer initially marketed the cough suppressant developed eleven days later by Hoffmann, diacetylmorphine (DAM) , which has become known as heroin , because it was assumed after human trials that aspirin had too many side effects.

  • Product presence in a US drugstore (2018)

  • Advertisement for aspirin tablets in the Tiroler Volksbote (South Tyrol) from October 28, 1926

  • Packaging, around 1940

Chemical and physical properties

Macro shot of ASA crystals recrystallized from water

Acetylsalicylic acid is a white powder or forms flat to needle-shaped crystals with a faint odor of acetic acid. The pKa value is 3.5. It melts at a temperature of 136 ° C, at temperatures above 140 ° C decomposition occurs. Acetylsalicylic acid is readily soluble in ethanol and alkali, but poorly soluble in benzene or cold water (3.3 g · l −1 at 20 ° C), which is due to the hydrophobic benzene ring. The water solubility increases considerably when heated. Because of their considerably better solubility in water, magnesium and calcium salts are also used therapeutically . The density of acetylsalicylic acid is 1.35 g · cm −3 , the vapor pressure is low.

Manufacturing

ASS crystals

The phenolic hydroxy group in ortho -position to the carboxyl group of the salicylic acid reacts with acetic anhydride acetylation , wherein the hydrogen of the hydroxyl group by an acetyl group is replaced.

ASA synthesis

For this purpose, industrially produced salicylic acid is esterified ( acetylated ) on the phenolic hydroxyl group with protonated acetic anhydride by means of the Kolbe-Schmitt reaction to give acetylsalicylic acid . Alternatively, the reaction product of the Kolbe-Schmitt reaction (sodium salicylate) can also be acetylated directly with acetic anhydride , resulting in acetylsalicylic acid and sodium acetate in a stoichiometric amount.

Typical by-products of all ASA syntheses are the condensation products acetylsalicylic anhydride (ASN), o -acetylsalicylsalicylic acid (ASSA), o- salicoylsalicylic acid (SSA) and disalicylide, they must be removed by subsequent crystallization.

pharmacology

Quaternary structure of the COX-2 molecule inhibited by ASA

Effects

Acetylsalicylic acid works by inhibiting the cyclooxygenase COX-1 and COX-2 .

Systemic effects

Pain relieving, anti-rheumatic, anti-pyretic and anti-inflammatory

Acetylsalicylic acid inhibits platelet aggregation even in small doses (30–50 mg) by inhibiting the cyclooxygenase COX-1 , with increasing doses (0.5–2 g) by inhibiting the cyclooxygenase COX-1 and COX-2 and the resulting decrease in the formation of Prostaglandins also decentralized analgesic, anti- rheumatic and antipyretic and finally (2–5 g) anti-inflammatory .

Reduction in gastric acid secretion

Prostaglandins are also involved in regulating gastric acid secretion and gastric mucosal blood flow, so that by inhibiting prostaglandin synthesis at higher doses and longer-term ASA intake, for example in the context of the treatment of rheumatic complaints, stomach complaints and gastric bleeding can occur.

The gastric intolerance is largely based on the (desired) systemic inhibition of prostaglandin synthesis and can at best be alleviated by other forms of administration (enteric tablets, suppositories or intravenous administration). However, a pharmaceutical form that releases the active ingredient lying on the gastric mucosa additionally impairs the tissue of the stomach for a short time.

Tumors

By inhibiting prostaglandin synthesis, acetylsalicylic acid can also prevent benign intestinal tumors from turning into cancer. Melanoma could also be prevented by taking ASA regularly.

For short-term use in doses of 500 to 1000 mg for acute pain, acetylsalicylic acid is comparable in its tolerance to other painkillers available in pharmacies.

Mechanism of action

Acetylation of a serine residue of prostaglandin H 2 synthase-1 by acetylsalicylic acid

The functionality of acetylsalicylic acid, namely the inhibition of prostaglandin production, was elucidated in 1971 by John Robert Vane , for which he received the Nobel Prize for Medicine in 1982 together with Sune Bergström and Bengt Samuelsson :

The effect of acetylsalicylic acid is based on an irreversible inhibition of prostaglandin H 2 - synthase , more precisely the cyclooxygenases, COX-1 and COX-2 . These enzymes catalyze the formation of inflammation-enhancing prostaglandins and z. B. Thromboxane A 2 , the u. a. has a platelet activating effect. During inhibition, acetylsalicylic acid transfers an acetyl residue to an amino acid residue ( serine 530) just before the catalytic center. As a result, the arachidonic acid, as the substrate of the enzyme, can no longer reach the active center and the enzyme is permanently inactivated. The COX-1 is inhibited about 10 to 100 times more strongly than the COX-2 by acetylsalicylic acid. Since platelets cannot reproduce enzymes due to the lack of a cell nucleus, the anticoagulant effect on them is irreversible - the duration of action is therefore the same as the survival time of the platelets (8-11 days).

Another indirect mechanism of action seems to be the indirect inhibition of cyclooxygenase : Acetylsalicylic acid effectively increases the activity of the cytochrome P450 isoforms CYP2E1 and CYP4A1, which break down arachidonic acid into epoxyeicosatrienoic acids . Some of these epoxyeicosatrienoic acids belong to the group of endogenous antipyretics , i.e. substances in the body that limit the fever reaction ; they inhibit cyclooxygenase-2 more effectively than aspirin itself.

Pharmacokinetics

Acetylsalicylic acid undergoes extensive first-pass - metabolism (some of them already in the stomach and intestinal wall by special esterases ) and has an oral bioavailability of approximately 70%. It is converted into the main metabolite salicylic acid in the body within 15 minutes . In the blood it binds to albumin by 50–70% .

Side effects and contraindications

The side effects that occur with analgesic dosing are usually of a minor nature: nausea, heartburn and vomiting are observed relatively frequently. In asthmatics , acetylsalicylic acid can be the cause of seizures, which can be explained by the fact that, due to the inhibition of cyclooxygenases, there is an oversupply of arachidonic acid , which then promotes the formation of bronchoconstrictor (the bronchial constriction) leukotrienes . A cross reaction to other pain relievers such as ibuprofen , diclofenac or naproxen is common.

The drug commission of the German medical profession points out that acetylsalicylic acid can cause irritation of the mucous membranes, bleeding in the gastrointestinal tract and stomach ulcers if taken regularly. In the case of inflammatory bowel disease ( Crohn's disease , ulcerative colitis ), caution should be exercised, as acetylsalicylic acid can cause relapses.

In order to have a positive influence on the above-mentioned ADRs , antioxidants such as B. Researched tocopherols and tocotrienols .

In children and adolescents with febrile illness aspirin should not be used since it (possibly after recovering from viral disease), the sometimes fatal syndrome Reye could trigger; alternative substances - such as paracetamol or ibuprofen  - should be used. In the UK, the over-the-counter supply of acetylsalicylic acid to children and adolescents under the age of 16 is prohibited for this reason. A suppressive effect on the unspecific immune system is also being discussed, since the immune modulator deoxycholic acid (literature) can only become active after the effects of acetylsalicylic acid have subsided. Nevertheless, there are clinical pictures even in childhood for which treatment with acetylsalicylic acid is definitely indicated. These include rheumatic fever or Kawasaki syndrome .

Acetylsalicylic acid may only be administered in small amounts during pregnancy, as ASA can lead to premature closure of the ductus arteriosus of the unborn child, especially in the third trimester . In addition, the inhibited clotting of blood increases the mother's tendency to bleed at birth.

In 1999, the number of aspirin-related pain reliever fatalities among Americans was estimated at 16,500 annually.

In 2004, aspirin hit the headlines because a large study with 88,000 participants ( Nurses' Health Study ) showed a connection between long-term and frequent use of aspirin and pancreatic cancer . In a previous study with 28,000 participants ( Iowa Women's Health Study ), an opposite effect was shown for aspirin, namely that regular intake protects against pancreatic cancer. An even larger study by the American Cancer Society with a total of 987,000 participants showed, however, that aspirin has neither a promoting nor a protective effect with regard to pancreatic cancer. This applies to both women and men.

A British meta-analysis in 2010 showed a clear, significant reduction in the incidence of colon cancer - and possibly other types of cancer - with daily intake of ASA. The patient data from 7 studies (23,535 patients, 657 deaths from cancer) were analyzed. It has been shown that long-term intake (at least 5 years) of aspirin leads to a reduction in cancer deaths regardless of the dose (75 mg or more), gender or smoking behavior, with the effect increasing with increasing age of the test subjects and prolonging the duration of intake . Both gastrointestinal (eg, colorectal cancer or esophageal cancer ) and non-gastrointestinal cancers (such as lung cancer ) performed less often to death with long-term aspirin use (up to 20 years was analyzed). The effect was particularly pronounced in adenocarcinomas (gastrointestinal and non-gastrointestinal). Taking aspirin daily for 5–10 years, taking into account the side effects of ASA, would lead to a reduction in deaths during this time of around 10%.

In asthmatics , the proportion of patients with ASA intolerance is around 8 to 20% and in patients with nasal polyps around 6% to 15%. This allergy is known as the Samter triad . A genetic (hereditary) predisposition is suspected.

In a Swedish study, published in August 2009 in the specialist journal Pharmacoepidemiology and Drug Safety , with 58,465 study participants, it was found that the use of aspirin in diabetic patients without any signs of cardiovascular disease led to increased mortality using the mortality register and the drug use documented in the patient register . However, a reduction in mortality has been observed with the use of aspirin in diabetic patients with signs of cardiovascular disease. The previous practice of using aspirin in diabetics without cardiovascular symptoms should then be revised until further findings from ongoing studies are available.

As a study published in Switzerland in 2010 showed, regular intake of aspirin can not only lead to frequent nosebleeds; Patients who took aspirin for heart disease prophylaxis at doses of 100 mg and 300 mg daily had more severe nosebleeds than comparable patients who did not take aspirin and required more surgical treatment.

In animal experiments on rats, according to the Red List, there were indications of a possible teratogenic ( teratogenic ) effect of chronic ingestion of ASA during pregnancy.

Physicians at the University of Sydney published a study in the Journal of the American Medical Association (JAMA) in 2013, which suggests that regular intake of aspirin is responsible for retinal damage ( macular degeneration (AMD)).

An Australian long-term study published on October 18, 2018 by Monash University in Melbourne, which was published in the US journal The New England Journal of Medicine , found that taking acetylsalicylic acid had negative effects on life. The consumption of the drug by healthy patients is often completely superfluous. A meta-analysis published on January 22, 2019 by scientists from King's College London in the US journal of the American Medical Association (JAMA) with 164,225 test subjects from a total of 13 clinical test series came to the conclusion that the use of acetylsalicylic acid (ASA, aspirin) was responsible for People without cardiovascular disease with a lower risk of cardiovascular events ( hazard ratio , 0.89; absolute risk reduction , 0.38%) and an increased risk of major bleeding (hazard ratio, 1.43; absolute risk increase, 0, 47%) is connected. The German Heart Foundation advises ASA intake as antiplatelet agents only in patients with a significant risk profile for heart attack or stroke.

Drug interactions and interactions

Due to the frequency of the simultaneous use of ASA and vitamin E preparations , the possible drug interaction with regard to the effects on the coagulation system is given greater attention and a thorough control of the coagulation parameters is recommended. Health aspects of a possible increased bleeding tendency under co-medication with tocopherol preparations have been discussed in the literature for some time.

Furthermore, there has recently been increasing evidence that acetylsalicylic acid and certain other painkillers from the group of non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs (NSAIDs) as well as paracetamol can reduce the effectiveness of vaccines because the body produces fewer protective antibodies after a vaccination . The latter is attributed to the fact that drugs such as acetylsalicylic acid 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.

Misuse in the event of injuries

Acetylsalicylic acid is unsuitable as a pain reliever for suppressing wound pain, such as after surgical interventions or injuries, since the anticoagulant effect lasts up to about seven days after the last dose and thus promotes bleeding. Because of the irreversible inhibition of cyclooxygenase in the platelets, it is also not possible to administer an antidote to immediately remove the anticoagulant . Rather, you have to wait until new, functional platelets are formed by the body . In this way, ingested acetylsalicylic acid can thwart a planned medical operation due to the increased risk of bleeding . In particularly urgent cases, the anticoagulant effect of acetylsalicylic acid can be partially reversed by administering platelet concentrates .

Misuse in cases of retinal vein occlusion

There is a widespread custom among ophthalmologists to prescribe aspirin as an additional drug in the treatment of patients with retinal vein occlusion, i.e. central vein occlusion (ZZV) or branch vein occlusion (VAV) in the retina of the eye. The reason for its widespread use lies in the proven effect of aspirin on major systemic thromboses of the veins . It was therefore believed that it could be similarly useful for retinal vein occlusions.

However, a comprehensive study of nearly 700 patients showed that aspirin and other anticoagulants ( anticoagulants ) had an adverse effect on the development of vision in patients with CRF, rather than any protective or healing properties. Several expert groups, including the Royal College of Ophthalmologists in London, spoke out against the use of these drugs (including aspirin) in patients with retinal vein obstruction.

Areas of application

Acetylsalicylic acid is not only used as a pain reliever, to lower fever and as an anti-inflammatory drug, but above all in low doses to inhibit platelet aggregation and thus to prevent new heart attacks and strokes (secondary / tertiary prophylaxis ) in the case of known arteriosclerotic vascular changes.

Not suitable for primary prevention in healthy patients

However, acetylsalicylic acid is not suitable for the primary prevention of healthy patients with an increased cardiovascular risk - this was proven by three studies in 2018. The American Heart Association and the American College of Cardiology then decided to change the guidelines for clinical practice. Acetylsalicylic acid often causes bleeding in the gastrointestinal tract. Nevertheless, millions of people continue to take low-dose acetylsalicylic acid daily, even without a doctor's prescription.

ASS is used in combination e.g. B. with clopidogrel also used in patients with fresh stents in the coronary arteries to avoid an occlusion ( stent thrombosis ). ASA is also part of the standard therapy for emergency treatment of acute coronary syndrome, such as heart attacks. In a study, intravenous administration of ASA was found to be more advantageous than oral administration in these cases.

Because of its positive effects on polycythemia vera , aspirin has been granted orphan drug status by the European Commission .

Resistance discussion

Acetylsalicylic acid resistance of varying degrees was found in a small study, whereby the dosage form also has an influence. Because of this, there is controversy over the introduction of devices to test for acetylsalicylic acid resistance in patients in need of an anticoagulant . If the test is positive, the conclusion would be to prescribe another anticoagulant (e.g. to prevent new infarcts ). Clopidogrel is a candidate for this, but it is about 100 times more expensive than acetylsalicylic acid. For this reason, the pharmaceutical industry has a strong motivation to advertise the introduction of acetylsalicylic acid resistance tests , while health insurance companies and sometimes doctors are rather reluctant to do so.

Other uses, flux for soft soldering

Acetylsalicylic acid is also used as a flux in soft soldering .

toxicity

High doses, for example 10 g ASA in adults, can lead to life-threatening metabolic acidosis (hyperacidity) with respiratory paralysis and unconsciousness. In addition, the inner ear can be damaged, which manifests itself in a hearing loss or tinnitus . Kidney damage has also been described ( analgesic nephropathy ).

Expired preparations or preparations that smell of vinegar should no longer be used. The latter were probably exposed to great heat and moisture, which not only adversely affects the effect, but also produces phenolic degradation products that are toxic to the stomach through autocatalytic decomposition.

Side effects of the pain reliever group around ASA, the non-opioid analgesics (i.e. together with paracetamol , ibuprofen, etc.) are among the 16 most common causes of death in the USA. However, since the number of victims of over-the-counter painkillers is not listed individually in statistics, the public takes the dangers of v. a. habitual or long-term use hardly true.

The CLP regulation with the H-phrase harmful to health when swallowed refer to larger amounts of the active ingredient as they are handled during its production, but of course not to the amounts in finished tablets when they are ingested according to the package insert.

The mean lethal dose (LD 50 ) for oral ingestion in rats is 200 mg / kg body weight.

proof

In order to chemically detect acetylsalicylic acid, it is first split into salicylic acid and acetic acid by means of alkaline or acidic hydrolysis . When the catalyst is in accordance with sodium hydroxide or hydrochloric acid, in which the substance is cooked used. Without heating, only the sodium salt is formed in the sodium hydroxide solution, which goes into solution due to its ionic properties, but does not react. After hydrolysis, the released salicylic acid can be detected using iron (III) chloride (FeCl 3 ) (a red-violet chelate complex is formed ) or a hydroxamic acid reaction . The determination of acetate or acetic acid is carried out by odor test, esterification with chloroethane (formation of characteristic smelling ethyl acetate ) or addition of lanthanum (III) nitrate (La (NO 3 ) 3 ), and iodine (blue staining).

The qualitative and quantitative determination of acetylsalicylic acid in pharmaceutical preparations or in blood plasma is preferably carried out by chromatographic methods such as, for. B. HPLC , gas chromatography or gas chromatography with mass spectrometry coupling . The highly specific analysis of salicylic acid - as a metabolic product in human serum - can be carried out using HPLC with fluorescence detection.

literature

Web links

Wiktionary: Acetylsalicylic acid  - explanations of meanings, word origins, synonyms, translations
Wiktionary: Aspirin  - explanations of meanings, word origins, synonyms, translations
Commons : Aspirin  - collection of pictures, videos and audio files

Individual evidence

  1. ↑ a b c d e f Entry on O-acetylsalicylic acid in the GESTIS substance database of the IFA , accessed on January 9, 2019(JavaScript required) .
  2. ↑ On the problem of thermal conversion during the melting point measurement, see H. Erdmann: γ-Oxycarbostyril from Antranilic Acid . In: Reports of the German Chemical Society . Vol. 32, volume 3 . F. Friedländer, Berlin 1899, p. 3572 f . ( Digitized on Gallica ).
  3. ↑ Patent DE134234 : Method for the preparation of salicylid. Published September 1, 1901 , Applicant: Hoffmann-La Roche . And R. Anschütz: About a new disalicylide. In: Ber. d. German Chem. Ges. 52, 1919, pp. 1875-1895, namely p. 1883; doi: 10.1002 / cber.19190520911 .
  4. ↑ Entry on Aspirin®. In: Römpp Online . Georg Thieme Verlag, accessed on May 21, 2014.
  5. ↑ Swiss Accident Insurance Fund (Suva): Limits - Current MAK and BAT values (search for 50-78-2 or acetylsalicylic acid ), accessed on September 16, 2019.
  6. ↑ a b Entry on acetylsalicylic acid in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  7. ↑ H. Bekemeier: Salicylamide and salicylic acid poisoning in cats in comparison with other animals. I. In: drug research . 5, 1955, pp. 572-575. PMID 13276287 .
  8. ↑ a b Walter Sneader: The discovery of aspirin: a reappraisal. In: BMJ. 321 (7276), Dec 23, 2000, pp. 1591-1594. PMC 1119266 (free full text).
  9. ↑ Christina Schott, Eva Maria Feller, ASPIRIN - A Neverending Story , University of Bayreuth, July 25, 2018. Retrieved on August 2, 2019.
  10. ↑ Karsten Schrör, HK Breddin: Acetylsalicylic acid in the cardiovascular system: 50 years after Felix Hoffmann . Springer DE, 1996, ISBN 3-7643-5646-4 , pp. 8 ( limited preview in Google Book search).
  11. ↑ Pharmavista - database of international finished medicinal products .
  12. ↑ Contra-Pain® plus . May 25, 2016. Retrieved July 27, 2018.
  13. ↑ z. BK-C. Bergmann, J. Ring (Ed.): History of Allergy. Verlag Karger Medical and Scientific Publishers, 2014, p. 132 ( limited preview in Google book search); Adrian Kerr: Ancient Egypt and Us: The Impact of Ancient Egypt on the Modern World. 2009, p. 100 f. ( limited preview in Google Book search).
  14. ↑ a b O. Lafont: From the willow to aspirin. In: Rev Hist Pharm. (Paris). 55 (354), Jul 2007, pp. 209-216. PMID 18175528 .
  15. ^ Charles F. Gerhardt: VII. — On some new compounds of salicylic. In: QJ Chem. Soc. 7, 1855, pp. 60-62, doi: 10.1039 / QJ8550700060 .
  16. ↑ H. Hlasiwetz, Hugo v. Gilm: Acetyl derivatives of phloretic and salicylic acid. In: Annals of Chemistry and Pharmacy. 112, 1859, pp. 180-182.
  17. ↑ K. Kraut: About salicylic compounds. In: Annals of Chemistry and Pharmacy. 150, 1869, pp. 1–20, namely p. 9 ff.
  18. ↑ Hugo Schiff: About anhydrides of salicylic acid . In: Annals of Chemistry and Pharmacy . tape 163 , 1872, pp. 218-228 ( archive.org ).
  19. ↑ M. Bialobrzeski, M. Nencki: Ueber die acetalicylic acid . In: Reports of the German Chemical Society . Vol. 30, volume 2 . F. Friedländer, Berlin 1897, p. 1776–1779 ( digitized on Gallica ). - CAS no. 13110-96-8 (melting point 215-216 ° C).
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