Acetylcysteine

Structural formula
General
Non-proprietary name	Acetylcysteine
other names	L- α-acetamido-β-mercaptopropionic acid ( R ) -2-acetylamino-3-sulfanylpropanoic acid ACC N -acetylcysteine ​​(NAC) ( R ) - N -acetylcysteine L - N -acetylcysteine N -acetyl- L -cysteine Acetylcysteinum ACETYL CYSTEINE ( INCI )
Molecular formula	C 5 H 9 NO 3 S
Brief description	White crystalline solid
External identifiers / databases
CAS number 616-91-1 EC number 210-498-3 ECHA InfoCard 100.009.545 PubChem 12035 ChemSpider 11540 DrugBank DB06151 Wikidata Q375613
Drug information
ATC code	R05 CB01 V03 AB23 S01 XA08
Drug class	Expectorans
Mechanism of action	Cleavage of the disulfide bridges of the secretion in the bronchi
properties
Molar mass	163.20 g mol −1
Physical state	firmly
Melting point	106-108  ° 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 no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
Toxicological data	5050 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Acetylcysteine (abbreviated ACC , NAC ; outdated mercapturic acid ) is a synthetic chemical compound . It is used as a drug in respiratory diseases with stuck sputum , i.e. H. used as a cough remover ; however, its effectiveness is controversial.

Acetylcysteine ​​has its best-documented effect as an antidote to paracetamol intoxication. In addition, acetylcysteine ​​is used off-label in nephrology , infectious diseases and psychiatry .

Pharmacological and toxicological properties

Acetylcysteine ​​is a derivative of the naturally occurring amino acid cysteine . Its plasma half-life is approximately one hour. After oral administration, acetylcysteine ​​is subject to a pronounced first-pass effect , whereby it is deacetylated to L- cysteine. The active substance and its metabolite are said to have a mucus-thinning ( secretolytic or mucolytic) and expectorant (secretomotor) effect in the bronchial tract. The effect is said to come about by splitting disulfide bridges that occur in the mucopolysaccharides that make up the secretion formed in the bronchi . The viscous mucus stuck in the bronchi should be able to be coughed up better through liquefaction. An anti-inflammatory effect is discussed as an alternative mechanism of action, which is supposed to be based on the ability of the reactive SH group of acetylcysteine to bind chemical radicals .

Acetylcysteine ​​also provides the body with cysteine , which it needs to produce glutathione . Glutathione plays an important role in the biotransformation of harmful substances ("detoxification"). Especially when paracetamol is broken down by cytochrome P450 , N- acetyl- p -benzoquinone imine is produced , which destroys liver cells and is neutralized by glutathione.

Acetylcysteine ​​inhibits the expression of prostaglandin E2 and COX-2 in vitro , which is possibly due to its effect as an antioxidant and the associated influence on the redox-sensitive transcription factor NF-kB .

Acetylcysteine ​​is largely non-toxic and has few undesirable effects. This has been shown in preclinical studies. For example, oral administration of 300 mg per kg of body weight of the active ingredient over 52 weeks did not lead to any changes in the health of dogs.

A human clinical study showed that a daily dose of 11.6 g acetylcysteine ​​orally over a period of three months did not lead to serious side effects.

A stimulation of glutathione production in the liver through the administration of acetylcysteine ​​(as a cysteine ​​donor ) was associated with possible health risks in healthy control persons in an EFSA opinion from 2004.

In the intravenous acetylcysteine ​​treatment of paracetamol poisoning in humans, there is experience with maximum daily doses of up to 30 g acetylcysteine. The intravenous administration of very high amounts of acetylcysteine ​​has led to partially irreversible anaphylactoid reactions , especially when administered quickly . In one case, epileptic seizures and cerebral edema resulting in death were reported after massive intravenous overdose .

Acetylcysteine derivatives are degradation products of the condensation products of glutathione with foreign substances in the human body (as part of biotransformation ) and can be detected in urine .

history

In 1960 it was found that thiols have an expectorant effect. The effect is particularly pronounced in connection with cysteine . Due to the sensitivity of cysteine ​​to oxidation , N- acetylcysteine ​​was used.

AL Sheffner demonstrated the mucolytic properties of N -acetylcysteine ​​in 1963, and Sprince showed in 1986 that its use in smokers has a pulmonary protective effect.

presentation

The salt L- cysteine hydrochloride, which is more resistant to oxidation, is used as the starting material, since L-cysteine is easily oxidized to cystine even by atmospheric oxygen . Enamelled steel containers with a capacity of 4–10 m³ have proven themselves as reaction vessels. The highly concentrated aqueous solution of the hydrochloride is first neutralized under a nitrogen protective atmosphere and constant cooling with 40% sodium hydroxide solution to approx. PH 7.5 (starting pH approx. 1) and then the acetyl group is added slowly at the same time with acetic anhydride coupled to the nitrogen atom. The reaction mixture now contains high concentrations of N-acetylcysteine, NaCl and free acetic acid. In order to isolate the very water-soluble N- acetylcysteine, the acetic acid must first be drawn off in a vacuum evaporator at approx. 70 ° C. The concentration of N- acetylcysteine ​​increases to several 100 g / l. Most of the NaCl formed during the reaction separates out as soon as it is evaporated. In contrast to N- acetylcysteine , its solubility in water hardly increases with increasing temperature.

The concentrate thus formed is then diluted again with a little water in order to keep the NaCl contained in solution during the subsequent cooling, while the N- acetylcysteine ​​crystallizes out and is then separated off by centrifugation.

The crude product is purified again by dissolving it in hot, pure water and filtration through activated charcoal and then crystallized, centrifuged, washed and dried by subcooling the solution and introducing high-purity seed crystals. The drying step is crucial for the storage stability and purity of the product and is expediently carried out under a protective atmosphere.

Due to the excellent water solubility of N -acetylcysteine, the mother liquors obtained in the intermediate steps are returned to the individual process steps, which places considerable demands on the logistical infrastructure for the quantities of liquid produced. In addition, large amounts of water have to be evaporated at low temperatures, which requires a lot of energy.

The high sensitivity of cysteine ​​and N- acetylcysteine ​​to oxidation is just as problematic . Even the slightest traces of iron (II) ions catalyze the oxidation of the thiol group of cysteine ​​to the disulfide compound cystine.

application areas

Respiratory diseases

Acetylcysteine ​​is a widely used active ingredient for liquefying mucus and promoting expectoration when coughing. It is administered orally , inhalatively or parenterally .

The efficacy of acetylcysteine ​​in terms of a mucus-thickening effect has not been proven for simple respiratory infections. The therapeutic effectiveness in bronchitis is controversial, since the studies from the 1980s do not meet today's demands on a study design. Accordingly, according to the DEGAM guideline, there is also no recommendation for ACC in the treatment of a flu-like infection or acute bronchitis, since randomized double-blind placebo-controlled studies could not demonstrate any significant effects on lung function, bronchial mucus, systemic oxygenation and / or the need for ventilation. The use of ACC as an expectorant is therefore critically questioned from a medical point of view.

In cystic fibrosis , a disease that is accompanied by a strong build-up of thick mucus in the bronchial tubes, high doses of acetylcysteine ​​seem to improve the symptoms.

Antidote for overdoses

Acetylcysteine ​​has been shown to be effective as an antidote for poisoning or overdosing with paracetamol or acrylonitrile . Very high doses are used for inpatient treatment, with ACC being given orally for 72 hours or intravenously for 20 to 21 hours . The is oral administration as effective as the intravenous, but worse tolerated as nausea and vomiting. At least in Europe, intravenous administration is preferred. Therapy is most effective when started less than eight hours after paracetamol intake. ACC is also recommended as an antidote in all phases of pregnancy.

Amino acid intake

Acetylcysteine ​​is often a component of infusion solutions for parenteral amino acid supply in renal insufficiency, liver insufficiency, hepatic encephalopathy and in dialysis patients.

Other (off-label use)

Nephrology

Outside of permitted areas of application, d. H. in off-label use , acetylcysteine ​​is used to prevent acute kidney failure in high-risk patients prior to X-ray procedures with contrast media. Here 2 × 600 mg are given on the day before the examination and on the day of the examination. The effectiveness of this measure is controversial. While a few studies found that acetylcysteine ​​prophylaxis was highly effective, the majority of the studies did not show any significant effect.

Infectious diseases

Animal experiments on mice have shown that ACC increases the survival rate after infection with malaria pathogens - parasites of the genus Plasmodium - from 20 to 100 percent. The body is enabled to protect the liver cells from excess free heme , which is released into the blood when red blood cells are destroyed. Studies have not proven whether the active ingredient also helps people with malaria.

The effect of acetylcysteine ​​as an antioxidant was investigated in an animal study. The authors conclude from their studies that ACC could have a beneficial effect on undesirable effects when using antibiotics. For quinolone antibiotics , aminoglycosides, and beta-lactam antibiotics , they found less damage to mitochondria with the additional administration of ACC. ACC apparently plays a role in maintaining the glutathione available in the cells , the most important endogenous antioxidant that was used up after 4 days without simultaneous administration of ACC when the antibiotics mentioned were used in mice. Further studies with which the results could also be transferred to humans are pending.

The use of acetylcysteine ​​in HIV and AIDS patients has been investigated in small studies. So far, no significant effects of ACC treatment on surrogate markers of the course of HIV disease such as viral load or the number of CD4 cells have been demonstrated. A statement from the professional associations and an official therapy recommendation for acetylcysteine ​​do not yet exist.

The use of acetylcysteine ​​in chronic prostatitis is under discussion in research circles. Muko proteins form a main component of the prostate secretion. The administration of a mucolytic is used to clean the glandular ducts of the prostate . This has so far been successfully tested in a few individual cases with ACC, but has not yet been clinically proven.

psychiatry

Acetylcysteine ​​is also playing an increasingly important role in psychiatry due to its effect on the glutamine metabolism in the brain. In particular, the use in schizophrenia , obsessive-compulsive disorder and depression is the subject of research.

ACC could play a role in drug therapy in the future. Animal studies have shown that cocaine addicted rats lost more motivation to administer the drug as a result of ACC than those given a placebo.

literature

• T. Ahola, V. Fellman, R. Laaksonen, J. Laitila, R. Lapatto, PJ Neuvonen, KO Raivio: Pharmacokinetics of intravenous N-acetylcysteine ​​in pre-term new-born infants. In: Eur J Clin Pharmacol . 55, 1999, pp. 645-650.
• GK Isbister, IK Bucens, IM Whyte: Paracetamol overdose in a preterm neonate. In: Arch Dis Child Fetal Neonatal Ed. 85, 2001, pp. F70-F2.

Trade names

Monopreparations

ACC (D, A, CH), Acemuc (D), Acemucol (CH), Acetyst (D), Aeromuc (A), Dynamucil (CH), Ecomucyl (CH), Fluimucil (D, A, CH), Helvetussin ( CH), Mucorben (A), Mucofluid (CH), Myxofat (D), NAC (D), Secresol (CH), Solmucol (CH), various generics (D, CH) Lysox (L)

Combination preparations

Alvesin (D), Aminopäd (D), Aminoplasmal (D), Deltamin (D), Infesol (D), Nephrotec (D), Periplasmal (D, A), Pädamin (A), Rinofluimucil (CH), Salviamin (D ), Solmucalm (CH)

Web links

• Entry on acetylcysteine at Vetpharm, accessed on August 25, 2020.

Individual evidence

1. ↑ Entry on ACETYL CYSTEINE in the CosIng database of the EU Commission, accessed on August 7, 2020.
2. ↑ ^{a b c d e} data sheet N-Acetyl-L-cysteine from Sigma-Aldrich , accessed on March 20, 2011 ( PDF ).
3. ↑ Acetylcysteine ​​and carbocysteine ​​to treat acute upper and lower respiratory tract infections in children without chronic broncho-pulmonary disease | Cochrane . May 31, 2013, doi : 10.1002 / 14651858.CD003124.pub4 ( cochrane.org [accessed June 23, 2017]).
4. ↑ ^{a b c d} Specialist information on NAC Sandoz® effervescent tablets ( Memento from October 19, 2013 in the Internet Archive ) (PDF, 43kB).
5. ↑ T. Origuchi, K. Migita, T. Nakashima, S. Honda, S. Yamasaki: Regulation of cyclooxygenase-2 expression in human osteoblastic cells by N-acetylcysteine . In: The Journal of Laboratory and Clinical Medicine . tape 136 , no. 5 , November 1, 2000, pp. 390-394 , doi : 10.1067 / mlc.2000.110369 , PMID 11079466 .
6. ↑ Yu Sun, Jie Chen, Basil Rigas: Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death. In: Carcinogenesis. 30, 2008, pp. 93-100, doi: 10.1093 / carcin / bgn242 .
7. ↑ T. Origuchi, K. Migita, T. Nakashima: Regulation of cyclooxygenase-2 expression in human osteoblastic cells by N-acetylcysteine. In: J Lab Clin Med. 136 (5), Nov 2000, pp. 390-394.
8. ↑ Erica Hoffer, Yelena Baum, A. Menahem Nahir: N-Acetylcysteine ​​enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes. In: Mediators of Inflammation. 11, 2002, pp. 321-323.
9. ↑ Michael J Morgan, Zheng-gang Liu: Crosstalk of reactive oxygen species and NF-κB signaling . In: Cell Research . tape 21 , no. 1 , January 1, 2011, p. 103–115 , doi : 10.1038 / cr.2010.178 , PMID 21187859 , PMC 3193400 (free full text).
10. ^ DC Plumb: Veterinary Drug Handbook. In: PharmaVet Publishing. White Bear Lake (USA), 1999.
11. ^ RE Johnston, HC Hawkins, JH Weikel Jr .: The toxicity of N-acetylcysteine ​​in laboratory animals. In: Semin Oncol . 10, Suppl 1, 1983, pp. 17-24.
12. ↑ H. Keller, A. Faulstich, M. Elker, M. Grell, S. Wuschko, JH Rehders: Clinical study on the effectiveness and tolerance of N-acetylcysteine ​​in the treatment of COB / COPD in horses. In: Practical Veterinarian. 82 (2), 2001, pp. 108-117.
13. ↑ Reduced glutathione (GSH) or GSH precursors such as N-acetylcysteine ​​(NAC)? ( Memento from February 10, 2013 in the Internet Archive ) Glutathione News
14. ↑ Opinion of the Scientific Panel on Food Additives, Flavors, Processing Aids and Materials in Contact with Food (AFC) on a request from the Commission related to N-Acetyl-L-cysteine ​​for use in foods for particular nutritional uses and in foods for spec. In: EFSA Journal. 2, 2004, p. 21, doi : 10.2903 / j.efsa.2004.21 .
15. ^ ^{A b} Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2nd, revised and expanded edition. Scientific contract company, Stuttgart 2005, ISBN 978-3-8047-2113-5 , p. 185 .
16. ↑ ^{a b c d} Deniz Cicek u. a .: Pharmacy training telegram: Acetylcysteine. ( Memento from October 6, 2014 in the Internet Archive ; PDF) Universität Düsseldorf, 7, 2013, pp. 60–74.
17. ↑ Medicinal prescription in practice . ( Memento of September 24, 2011 in the Internet Archive ; PDF; 397 kB) Volume 33, 3rd edition, July 2006.
18. ↑ R. Tirouvanziam u. a .: High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. In: PNAS 103, 2006, pp. 4628-4633. PMID 16537378 .
19. ↑ H. Kupferschmidt: Therapy of Paracetamol Poisoning ( Swiss Toxicological Information Center (PDF); PDF; 72 kB).
20. ↑ MJ Smilkstein, GL Knapp, KW Kulig, BH Rumack: Efficacy of oral N-acetylcysteine ​​in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) . In: N. Engl. J. Med. Band 319 , no. December 24 , 1988, pp. 1557-1562 , PMID 3059186 .
21. ^ LF Prescott, J. Park, A. Ballantyne, P. Adriaenssens, AT Proudfoot: Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine . In: The Lancet . tape 2 , no. 8035 , August 1977, p. 432-434 , PMID 70646 .
22. ↑ E. Kozer, G. Koren: Management of paracetamol overdose: current controversies . In: Drug Saf . tape 24 , no. 7 , 2001, p. 503-512 , PMID 11444723 .
23. ↑ B. Bailey: Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? In: Birth Defects Res Part A-Clin Mol Teratol . tape 67 , no. 2 , February 2003, p. 133-140 , doi : 10.1002 / bdra.10007 , PMID 12769509 .
24. ↑ Richard Dekhuijzen: N-Acetylcysteine and cytoprotective effects against bronchopulmonary damage: from in vitro studies to clinical application . In: Roberta Masella, Giuseppe Mazza (Ed.): Glutathione and Sulfur Amino Acids in Human Health and Disease . Wiley, 2009, ISBN 0-470-17085-9 , pp. 519-542 .
25. ↑ Steven Fishbane: N-Acetylcysteine ​​in the Prevention of Contrast-Induced Nephropathy . In: Clin J Am Soc Nephrol . No. 3 , 2008, p. 281-287 ( full text , abstract ).
26. ↑ E. Seixas, R. Gozzelino, A. Chora and a .: Heme oxygenase-1 affords protection against noncerebral forms of severe malaria . In: PNAS . tape 106 , no. 37 , September 2009, p. 15837-15842 , doi : 10.1073 / pnas.0903419106 , PMID 19706490 , PMC 2728109 (free full text).
27. ↑ With cough remover against malaria . In: Wissenschaft.de. August 18, 2009, accessed September 9, 2019 . 
28. ↑ Antibiotics: Long-term damage from oxidative damage to mitochondria . ( Memento from September 14, 2013 in the Internet Archive )
29. ↑ S. Kalghatgi, CS Spina, JC Costello, M. Liesa, JR Morones-Ramirez, S. Slomovic, A. Molina, OS Shirihai, JJ Collins: Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells. In: Science Translational Medicine. 5, 2013, pp. 192ra85–192ra85, doi: 10.1126 / scitranslmed.3006055 .
30. ↑ on the ACC hypothesis in chronic prostatitis . ( Memento from January 9, 2011 in the Internet Archive ; PDF; 3.6 MB) In: Laborjournal. 3, 2007, pp. 14-18.
31. ↑ Michael Berk, David Copolov, Olivia Dean, Kristy Lu, Sue Jeavons, Ian Schapkaitz, Murray Anderson-Hunt, Fiona Judd and others. a .: N-Acetyl Cysteine ​​as a Glutathione Precursor for Schizophrenia — A Double-Blind, Randomized, Placebo-Controlled Trial. In: Biological Psychiatry. 64 (5), 2008, pp. 361-368.
32. ↑ DL Lafleur et al. a .: N-acetylcysteine ​​augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. In: Psychopharmacology . Volume 184, Number 2, January 2006, pp. 254-256.
33. ↑ M. Berk, D. Copolov, O. Dean, K. Lu, S. Jeavons, I. Schapkaitz, M. Andersonhunt, A. Bush: N-Acetyl Cysteine ​​for Depressive Symptoms in Bipolar Disorder — A Double-Blind Randomized Placebo -Controlled Trial. In: Biological Psychiatry . 64 (6), 2008, pp. 468-475. doi: 10.1016 / j.biopsych.2008.04.022 . PMID 18534556 .
34. ↑ Eric Ducret, Mickaël Puaud, Jérôme Lacoste, Aude Belin-Rauscent, Maxime Fouyssac, Emilie Dugast, Jennifer E. Murray, Barry J. Everitt, Jean-Luc Houeto, David Belin: N-Acetylcysteine ​​Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake. In: Biological Psychiatry . doi: 10.1016 / j.biopsych.2015.09.019 . PMID 26592462 .

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