Acetylcysteine

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Acetylcysteine
Systematic (IUPAC) name
(R)-2-acetamido-3-mercaptopropanoic acid
Identifiers
CAS number	616-91-1
ATC code	R05CB01 S01 XA08 V03 AB23
PubChem	12035
DrugBank	n/a
Chemical data
Formula	C₅H₉N O₃S
Mol. mass	163.19
Pharmacokinetic data
Bioavailability	6–10% (oral) <3% (topical)
Metabolism	hepatic
Half life	5.6 hours (adults) 11 hours (neonates)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	B2 (Aus)
Legal status	Schedule 4 (Aus) OTC or Rx (U.S.)
Routes	inhalation, IV, oral

Acetylcysteine (rINN) (IPA: [ˌæsɛtl̩ˈsɪstin, əˌsɛtl̩-, ˌæsətaɪl-]), also known as N-acetylcysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of paracetamol overdose. For these indications, acetylcysteine is available under the trade names ACC (Hexal AG), Mucomyst (Bristol-Myers Squibb), Acetadote (Cumberland Pharmaceuticals), Fluimucil and Parvolex (GSK).

1 Dosage forms
2 Chemistry
3 Clinical use
4 Other uses
5 References
6 See also
7 External links

[edit] Dosage forms

Acetylcysteine is available in different dosage forms for different indications:

Solution for inhalation (Mucomyst, Mucosil) – inhaled for mucolytic therapy or ingested for nephroprotective effect
IV injection (Parvolex) – treatment of paracetamol overdose
Oral solution – various indications

The IV injection and inhalation preparations are generally prescription only, while oral solution is available over the counter in many countries.

[edit] 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.

[edit] Clinical use

[edit] 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. It is also used post-operatively, as a diagnostic aid, and in tracheostomy care. It may be considered ineffective in cystic fibrosis (Rossi, 2006). However, a recent paper in the Proceedings of the National Academy of Sciences (March 21st, vol. 103, no.12) 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 (Tirouvanziam et al. (2006)). 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).

[edit] Paracetamol overdose

Intravenous acetylcysteine is indicated for the treatment of paracetamol (acetaminophen) overdose. Oral acetylcysteine for this indication is uncommon as it is poorly tolerated owing to the high doses required (due to poor oral bioavailability), unpleasant taste/odour and adverse drug reactions (particularly nausea and vomiting).

For this indication, acetylcysteine acts to augment glutathione reserves (depleted by toxic paracetamol metabolites) in the body and, together with glutathione to directly bind to toxic metabolites. These actions serve to protect hepatocytes in the liver from toxicity due to paracetamol overdose.

[edit] 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 (Tepel et al 2000), while others appear to cast doubt on its efficacy (Hoffman et al., 2004; Miner et al., 2004). 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." (NEJM 2006; 354:2773-82) 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" (JAMA Vol. 289, No.5, pg. 553-558).

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

[edit] Other uses

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

NAC has been shown to reduce cravings associated with chronic cocaine use in a study conducted at the Medical University of South Carolina ( Kalivas, et al, 2006)
It may reduce the incidence of chronic obstructive pulmonary disease (COPD) exacerbations (Pela et al., 1999)
In the treatment of AIDS, NAC has been shown to cause a "marked increase in immunological functions and plasma albumin concentrations" (Breitkreutz & al, 2000). 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 (Ungheri et al., 2000)
Animal studies suggest that NAC may help prevent noise-induced hearing loss (Kopke et al., 2005). 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 and US Navy.
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 (Bachert et al., 2003).
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.

[edit] References

Bachert C, Hormann K, Mosges R, et al. An update on the diagnosis and treatment of sinusitis and nasal polyposis. Allergy 2003;58(3):176-91. PMID 12653791
Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004;15:407-10. Fulltext. PMID 14747387.
Kopke R, Bielefeld E, Liu J, et al. Prevention of impulse noise-induced hearing loss with antioxidants. Acta Otolaryngol 2005;125(3):235-43. PMID 15966690
Miner SE, Dzavik V, Nguyen-Ho P, Richardson R, Mitchell J, Atchison D, Seidelin P, Daly P, Ross J, McLaughlin PR, Ing D, Lewycky P, Barolet A, Schwartz L. N-acetylcysteine reduces contrast-associated nephropathy but not clinical events during long-term follow-up. Am Heart J 2004;148:690-5. PMID 15459602.
Pela R, Calcagni AM, Subiaco S, et al. N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD. Respiration 1999;66(6):495-500. PMID 10575333
Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180-4. PMID 10900277.
Ungheri D, Pisani C, Sanson G, et al. Protective effect of n-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol 2000;13(3):123-128. PMID 12657201
Breitkreutz R, Pittack N, Nebe CT, Schuster D, Brust J, Beichert M, Hack V, Daniel V, Edler L, Droge W. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. J Mol Med. 2000;78(1):55-62. PMID: 10759030 [1]