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N-acetylcysteine

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N-acetylcysteine

Template:Chembox ChEMBL
Acetylcysteine
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Template:Chemboximage
Identifiers
CAS number 26117-28-2 S YesY
PubChem 94364 S YesY
ChemSpider 85162 S YesY
UNII WYQ7N0BPYC YesY
EC number 230-609-9
DrugBank DB06151
KEGG D00221Template:Keggcite2
MeSH Acetylcysteine
ChEBI CHEBI:28939 YesY
RTECS number HA1660000 R
ATC code AB23
Beilstein Reference 1724426 R
Gmelin Reference 142554 R
Jmol-3D images Image 1
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 5050 mg kg−1 (oral, rat)
Related compounds
Related alkanoic acids
Related compounds N-Acetylglycinamide
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Acetylcysteine rINN /əˌsɛtəlˈsɪstn/, 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 that 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

Main article: Paracetamol poisoning

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 acetylcysteine did not include acetylation as a reason for the low bioavailability of acetylcysteine. In the research conducted by Baker,[4] it was concluded that oral 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 doses of intravenous 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, chronic obstructive pulmonary disease, and pulmonary fibrosis. 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 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 radiocontrast nephropathy,[12] whereas others appear to cast doubt on its efficacy.[13][14] Data published in two papers in the New England Journal of Medicine and the Journal of the American Medical Association. conclude:

  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]

A clinical trial from 2010, however, 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]

Acetylcysteine continues to be commonly used in individuals with renal impairment to prevent the precipitation of acute renal failure.

Treatment of cyclophosphamide-induced hemorrhagic cystitis

Acetylcysteine has been used for cyclophosphamide-induced hemorrhagic cystitis, although mesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide. [18] [19]

Microbiological use

Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for diagnosis of tuberculosis. It also displays significant antiviral activity against the influenza A viruses.[20]

Interstitial lung disease

Acetylcysteine is used in the treatment of interstitial lung disease to prevent disease progression.[21][22][23][24]

Psychiatry

Acetylcysteine has been shown to reduce the symptoms of both schizophrenia[25] and bipolar disorder[26] in two placebo controlled trials conducted at Melbourne University. It is thought to act via modulation of NMDA glutamate receptors or by increasing glutathione. Pilot data suggests potential efficacy in autism, cocaine craving, smoking, and obsessive symptoms.[27] Replicatory trials in bipolar disorder, schizophrenia, and depression are currently under way in Geelong, Australia conducted by Dr. Michael Berk of Barwon Health & Deakin University.[26][25]

Polycystic ovary syndrome

In a small prospective trial comparing acetylcysteine to metformin (which is the standard drug treatment for PCOS), both treatments resulted in a significant decrease in body mass index, hirsutism score, fasting insulin, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy.[28]

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.[29] 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, the equivalent of about 20 grams per day.[30][29] Nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[31]

Researchers from Anhui Medical University in China reported in 2006 that although N-acetylcysteine prevented liver damage when taken before alcohol, when taken 4 hours after alcohol it actually made liver damage worse in a dose-dependent fashion.[32]

Complexing agent

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.[33]

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.

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), Mucinac (Cipla India), Siran (MegaPharm, Israel / Temmler Pharma, Germany), Amuco200 (Camox Pharmaceuticals, South Africa), ACC200 (Hexal Pharma, South Africa).
  • Ocular solution - for mucolytic therapy
  • Sachet (600 mg) - Bilim Pharmaceuticals, trebon N (Uni-Pharma Greece)
  • 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:

  • Acetylcysteine has been successfully used to aid in the treatment of cannabis dependence in adolescents.[34]
  • Acetylcysteine has had anecdotal reports and some research suggesting efficacy in preventing nail biting.[35]
  • Acetylcysteine is being tested in a double blind trial in Systemic Lupus Erythematosus.[36] The objective is to correct mitochondrial dysfunction.
  • Acetylcysteine has been shown to reduce cravings associated with chronic cocaine use in a study conducted at the Medical University of South Carolina.[37][38]
  • It may reduce the incidence of chronic obstructive pulmonary disease (COPD) exacerbations.[39]
  • In the treatment of AIDS, acetylcysteine has been shown to cause a "marked increase in immunological functions and plasma albumin concentrations".[40] Albumin concentration are inversely correlated with muscle wasting (cachexia), a condition associated with AIDS.
  • A human study of 262 primarily elderly individuals indicates that acetylcysteine may decrease influenza symptoms. In the study, 25% of virus-infected subjects who received acetylcysteine treatment developed symptoms whereas 79% in the placebo group developed symptoms.[41]
  • Stability studies of carbocisteine in two differet dosage form, tablets and capsules.[39]
  • It has been suggested that acetylcysteine 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.[42]
  • 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.[43][44] A 2006 rodent study found that while pretreatment with acetylcysteine protected against ethanol-induced liver damage, post-treatment actually worsened ethanol-induced liver damage.[32]
  • It has been shown to help women with PCOS (polycystic ovary syndrome) to reduce insulin problems and possibly improve fertility.[45]
  • Small studies have shown acetylcysteine to be of benefit to sufferers of blepharitis.[46]
  • It has been shown to help trichotillomania,[47] a condition causing compulsive hair-pulling.
  • It has been shown effective in the treatment of Unverricht-Lundborg disease in an open trial in 4 patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with acetylcysteine treatment has been documented.[48]
  • Results of a research study published in the New England Journal of Medicine in November 2011, tested the effect of acetylcysteine in combination with glucocorticoids (combination group) for patients suffering from severe alcoholic hepatitis. The data showed that the combination of 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.[49]
  • Acetylcysteine appears to improve the clinical efficacy of B vitamins in patients with raised homocysteine and memory disorders, including dementia.[50]

References

External links

  • U.S. National Library of Medicine: Drug Information Portal - Acetylcysteine
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