Acetylcysteine

Acetylcysteine
IUPAC name 2-Acetamido-3-sulfanylpropanoic acid[1]
Other names Acetadote[citation needed] 2-Acetamido-3-mercaptopropanoic acid[citation needed]
Identifiers
CAS number	7218-04-4 N, 616-91-1 R Y, 26117-28-2 S Y
PubChem	581 Y, 12035 R Y, 94364 S Y
ChemSpider	561 N, 11540 R Y, 85162 S Y
UNII	WYQ7N0BPYC Y
EC number	230-609-9
DrugBank	DB06151
KEGG	D00221 Y
MeSH	Acetylcysteine
ChEBI	CHEBI:28939 Y
ChEMBL	CHEMBL600 Y
RTECS number	HA1660000 R
ATC code	R05CB01,S01XA08, V03AB23
Beilstein Reference	1724426 R
Gmelin Reference	142554 R
Jmol-3D images	Image 1
SMILES CC(=O)NC(CS)C(O)=O
InChI InChI=1S/C5H9NO3S/c1-3(7)6-4(2-10)5(8)9/h4,10H,2H2,1H3,(H,6,7)(H,8,9) N Key: PWKSKIMOESPYIA-UHFFFAOYSA-N N
Properties
Molecular formula	C5H9NO3S
Molar mass	163.19 g mol−1
Appearance	White, opaque crystals
Melting point	106-108 °C, 379-381 K, 223-226 °F
log P	−0.696
Acidity (pKa)	3.252
Basicity (pKb)	10.745
Pharmacology
Bioavailability	6–10% (oral) <3% (inhalational)
Routes of administration	Inhalational Intravenous Oral
Metabolism	Hepatic
Elimination half-life	5.6 hours (adults) 11 hours (neonates)
Excretion	renal
Licence data	US
Legal status	Prescription Only (S4)(AU) ℞-only(US)
Pregnancy category	B2(AU) B(US)
Hazards
S-phrases	S22, S24/25
LD50	5.050 mg kg−1 (oral, rat)
Related compounds
Related compounds	Tiopronin gamma-Glutamylcysteine
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Acetylcysteine rINN ( /əˌsɛtəlˈsɪstiːn/), also known as N-acetylcysteine or N-acetyl-L-cysteine (abbreviated NAC), is a pharmaceutical drug and nutritional supplement used primarily as a mucolytic agent and in the management of paracetamol (acetaminophen) overdose. Other uses include sulfate repletion in conditions, such as autism, where cysteine and related sulfur amino acids may be depleted.^[2]

Acetylcysteine is a derivative of cysteine; an acetyl group is attached to the nitrogen atom. This compound is sold as a dietary supplement commonly claiming antioxidant and liver protecting effects. It is used as a cough medicine because it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. It is also this action of breaking disulfide bonds that makes it useful in thinning the abnormally thick mucus in cystic and pulmonary fibrosis patients.

Medical uses

Paracetamol overdose

Intravenous acetylcysteine is indicated for the treatment of paracetamol (acetaminophen) overdose. When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to inactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, therefore damaging hepatocytes. This may lead to severe liver damage and even death by fulminant liver failure.

For this indication, acetylcysteine acts to augment the glutathione reserves in the body and, together with glutathione, directly bind to toxic metabolites. These actions serve to protect hepatocytes in the liver from NAPQI toxicity.

Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,^[3] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting. Studies conducted by Baker and Dilger^[4] suggest that the prior pharmacokinetic studies of N-acetylcysteine did not include acetylation as a reason for the low bioavailability of N-acetylcysteine. In the research conducted by Baker,^[4] it was concluded that oral N-acetylcysteine was identical in bioavailability to Cysteine precursors. However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting.^[5] Repeated overdoses of intravenous N-acetylcysteine will cause these allergic reactions to progressively worsen in these people.

Several studies have found this anaphylaxis-like reaction to occur more often in people given IV acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.^[6][7][8][9]

In some countries, a specific intravenous formulation does not exist to treat paracetamol overdose. In these cases, the formulation used for inhalation may be used intravenously.

Mucolytic therapy

Inhaled acetylcysteine is indicated for mucolytic ("mucus-dissolving") therapy as an adjuvant in respiratory conditions with excessive and/or thick mucus production. Such conditions include emphysema, bronchitis, tuberculosis, bronchiectasis, amyloidosis, pneumonia, cystic fibrosis and Chronic Obstructive Pulmonary Disease. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis.^[10] However, a recent paper in the Proceedings of the National Academy of Sciences reports that high-dose oral N-acetylcysteine modulates inflammation in cystic fibrosis and has the potential to counter the intertwined redox and inflammatory imbalances in CF.^[11] Oral acetylcysteine may also be used as a mucolytic in less serious cases.

For this indication, acetylcysteine acts to reduce mucus viscosity by splitting disulfide bonds linking proteins present in the mucus (mucoproteins).

Nephroprotective agent

Oral acetylcysteine is used for the prevention of radiocontrast-induced nephropathy (a form of acute renal failure). Some studies show that prior administration of acetylcysteine markedly decreases (90%) radiocontrast nephropathy,^[12] whereas others appear to cast doubt on its efficacy.^[13][14] Worth considering is the newest data published in two papers in the New England Journal of Medicine and the Journal of the American Medical Association. The authors' conclusions in those papers were:

1. "Intravenous and oral N-acetylcysteine may prevent contrast-medium–induced nephropathy with a dose-dependent effect in patients treated with primary angioplasty and may improve hospital outcome."^[15]
2. "Acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiographic procedures, with minimal adverse effects and at a low cost"^[16]

The latest clinical trial, whose results were announced in November 2010, has found that acetylcysteine is ineffective for the prevention of contrast-induced nephropathy. This trial, involving 2,308 patients, found that acetylcysteine was no better than placebo; whether acetylcysteine or placebo was used, the incidence of nephropathy was the same—13%.^{[17][citation needed]}

Acetylcysteine continues to be commonly used in individuals with renal impairment to prevent the precipitation of acute renal failure.^{[citation needed]}

Microbiological use

Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for diagnosis of tuberculosis.

Interstitial lung disease

Acetylcysteine is used in the treatment of interstitial lung disease to prevent disease progression.^{[18][19][20][21]}

Psychiatry

Acetylcysteine has been shown to reduce the symptoms of both schizophrenia^[22] and bipolar disorder^[23] in two placebo controlled trials conducted at Melbourne University. It is thought to act via modulation of NMDA glutamate receptors or by increasing glutathione. Replicatory trials in bipolar disorder, schizophrenia and depression are underway.

Adverse effects

Researchers at the University of Virginia reported in 2007 study using very large doses in a mouse model that acetylcysteine could potentially cause damage to the heart and lungs.^[24] They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (SNOAC), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia). The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in vivo.

The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans;^[24] nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.^[25]

Complexing agent

N-Acetylcysteine has been used to complex palladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzed coupling reactions.^[26]

Chemistry

Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals.

Trade names

In addition to being available as an over-the-counter nutritional supplement, acetylcysteine is also marketed under these trade names:

• ACC (Hexal AG)
• Acemuc (Betapharm, Germany)
• Acemuk (Investi, Argentina)
• Acetyst (Ristert, Germany)
• Acetadote (Cumberland Pharmaceuticals)
• Asist (Bilim Pharmaceuticals, Turkey)
• Bronkyl (Weifa, Norway)
• Brunac eyedrops (Bruschettini, Italy)
• Fluimucil (Zambon)
• Fluimukan (Lek, Slovenia)
• Flumil (Pharmazam, Spain)
• Flutafin (Shiteh, Taiwan)
• Lysox (Menarini)
• Mucinac (Cipla, India)
• Mucohelp (Neiss Labs, India)
• Mucolysin (Sandoz)
• Mucomelt-A (Venus Remedies, India)
• MUCOMIX (Samarth Life Sciences, India)
• Mucomyst (Bristol-Myers Squibb)
• NAC AL (ALIUD Pharma GmbH, Germany)
• Nytex (Pharos,Indonesia)
• Parvolex (GSK)
• PharmaNAC (BioAdvantex Pharma Inc., North America)
• Rheunac (Tree Of Life, Israel)
• Siran (Temmler Pharma, Germany)
• Solmucaïne (IBSA, Switzerland)
• Trebon N (Uni-pharma S.A.], Greece)
• Vlenolys (Intermed S.A.], Greece)

Dosage forms

Acetylcysteine is available in different dosage forms for different indications:

• Solution for inhalation (Assist,Mucomyst, Mucosil) – inhaled for mucolytic therapy or ingested for nephroprotective effect (to protect the kidneys)
• IV injection (Assist,Parvolex, Acetadote) – treatment of paracetamol/acetaminophen overdose
• Oral solution – various indications.
• Effervescent Tablets (200 mg) - Reolin (Hochland Pharma Germany), Solmucol (600 mg)(IBSA, Switzerland), Cystaline (Thailand), and Mucinac (Cipla India).
• Ocular solution - for mucolytic therapy
• Sachet (600 mg) - Bilim Pharmaceuticals
• CysNAC (900 mg) – NeuroScience Inc.
• PharmaNAC Effervescent Tablets (900 mg) - Bioadvantex Pharma.

The IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries.

Research

The following uses have not been well-established or investigated:

• Evidence that NAC and other antioxidants can exert beneficial effects on pancreatic b-cell function in diabetes was published in a 1999 study. The authors conclude that a sufficient supply of antioxidants (NAC, vitamin C plus vitamin E, or both) may prevent or delay b-cell dysfunction in diabetes by providing protection against glucose toxicity.^[27]

• NAC is undergoing clinical trials in the United States for the treatment of obsessive-compulsive disorder.^[28] It is thought to counteract the glutamate hyperactivity in OCD.
• NAC has had anecdotal reports and some research suggesting efficacy in preventing nail biting^[29]
• NAC is being tested in a double blind trial in Systemic Lupus Erythematosus.^[30]The objective is to correct mitochondrial dysfunction.
• NAC has been shown to reduce cravings associated with chronic cocaine use in a study conducted at the Medical University of South Carolina^[31][32]
• It may reduce the incidence of chronic obstructive pulmonary disease (COPD) exacerbations^[33]
• In the treatment of AIDS, NAC has been shown to cause a "marked increase in immunological functions and plasma albumin concentrations"^[34] Albumin concentration are inversely correlated with muscle wasting (cachexia), a condition associated with AIDS.
• An animal study indicates that acetylcysteine may decrease mortality associated with influenza^[35]
• Animal studies suggest that NAC may help prevent noise-induced hearing loss.^[36] A clinical trial to determine efficacy in preventing noise-induced sensorineural hearing loss in humans is currently (2006) being jointly conducted by the US Army^[37] and US Navy^[38]
• A human study of 262 primarily elderly individuals indicates that NAC may decrease influenza symptoms. In the study, 25% of virus-infected subjects who received NAC treatment developed symptoms, whereas 79% in the placebo group developed symptoms.^[39]
• It has been suggested that NAC may help sufferers of Samter's triad by increasing levels of glutathione allowing faster breakdown of salicylates, though there is no evidence that it is of benefit^[40]
• There are claims that acetylcysteine taken together with vitamin C and B₁ can be used to prevent and relieve symptoms of veisalgia (hangover following ethanol (alcohol) consumption). The claimed mechanism is through scavenging of acetaldehyde, a toxic intermediate in the metabolism of ethanol.^[41][42]
• It has been shown to help women with PCOS (polycystic ovary syndrome) to reduce insulin problems and possibly improve fertility.^[43]
• Small studies have shown acetylcysteine to be of benefit to sufferers of blepharitis^[44]
• Studies in mouse models of Ataxia Telangiectasia (ATM knockout) indicate that NAC prevents genomic instability and retards lymphomagenesis in these animals.^[45] Clinical trials in human AT patients are underway.^{[citation needed]}
• It has been shown to help trichotillomania,^[46] a condition causing compulsive hair-pulling as well as compulsive nailbiting.
• Sulfur and sulfur-related amino acids are commonly depleted in autism.^[2] Glutathione, which largely depends on cysteine for its formation, is also frequently depleted in autism,^[47] and may contribute to the heavy metal burden commonly found in autistic patients.^[48]
• Possible antidote for methylmercury poisoning. It produced an acceleration of urinary methyl-mercury excretion in mice^[49]
• It has been shown effective in Unverricht-Lundborg disease in an open trial in 4 patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with N -acetylcysteine treatment has been documented.^[50]
• Small reduction of cell death in chemotherapy patients, due to reduction in oxidative stress. Reduced ROS and lipid peroxidation, and restored of antioxidant enzyme activities.^[51]
• Results of a research study published the "New England Journal of Medicine" during November 2011 tested the effect of N-acetylcysteine in combination with glucocorticoids (combination group) for patients suffering severe alcoholic hepatitis. The data shows that the combination of N-acetylcysteine with prednisolone decreased mortality significantly at one month compared to the prednisolone only group (8% vs 24%, P=0.006). However, the improvement was not as significant at 3 months or 6 months (22% vs 34%, P=0.06) and (27% vs 38%, P=0.07). Factors that were associated with increased 6 month survival included younger age, shorter prothrombin time, lower levels of bilirubin in baseline studies, and decrease in bilirubin on day 14, all (P<0.001). Death due to hepatorenal syndrome occurred less frequently for the combination group at 6 months (9% vs 22%, P=0.02) and infections were also less frequent in the combination group as well (P=0.001). Six month survival, the primary outcome, was not improved in conclusion.^[52]

References

External links

• CIMS India database "[1]"
• N-acetylcysteine replenishes glutathione in HIV infection. "[2]"
• Stanislaus, Romesh; Gilg, Anne G; Singh, Avtar K; Singh, Inderjit (2005). "N-acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats.". Journal of Autoimmune Diseases 2 (1): 4. doi:10.1186/1740-2557-2-4. PMC 1097751. PMID 15869713. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1097751. 
• British National Formulary 55, March 2008; ISBN 978-0-85369-776-3
• U.S. National Library of Medicine: Drug Information Portal - Acetylcysteine
• Research based information on Acetylcysteine as a nutritional supplement