Acetylcysteine

Overview
Acetylcysteine (rINN; ), also known as N-acetylcysteine or N-acetyl-L-cysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of paracetamol (acetaminophen) overdose. For these indications, it is available under the trade names ACC (Hexal AG), Mucomyst (Bristol-Myers Squibb), Acetadote (Cumberland Pharmaceuticals), Fluimucil (Zambon), Parvolex (GSK), Lysox (Menarini) and Mucolysin (Sandoz).

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 (to protect the kidneys)
 * IV injection (Parvolex, Acetadote) – treatment of paracetamol/acetaminophen overdose
 * Oral solution – various indications

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

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 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).

Paracetamol (Acetaminophen) overdose
Intravenous acetylcysteine is indicated for the treatment of paracetamol (acetaminophen) overdose. When paracetamol is taken in large quanities, a minor metabolite called N-methyl-p-benzoquinone imine (NAPQI) builds up. It is normally conjugated by glutathione, but when taken in excess (especially in alcoholics), 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 uncommon, as it is poorly tolerated, owing to the high doses required (due to low oral bioavailability), very unpleasant taste and odour, and adverse effects (particularly nausea and vomiting). 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 (Kanter, 2006). Repeated overdoses will cause the allergic reaction to get worse and worse. 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 (Dawson et al., 1989; Bailey & McGuigan, 1998; Schmidt & Dalhoff, 2001; Lynch & Robertson, 2004).

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.

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), whereas 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." (Marenzi et al, 2006) 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" (Kay et al., 2003).

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

Investigational
The following uses have not been well-established or investigated:
 * NAC is undergoing clinical trials in the United States for the treatment of obsessive-compulsive disorder. It is thought to counteract the glutamate hyperactivity in OCD.
 * NAC has been shown to reduce cravings associated with chronic cocaine use in a study conducted at the Medical University of South Carolina (Mardikian et al, 2007; LaRowe et al, 2007)
 * 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.
 * It has been shown to help women with PCOS (polycystic ovary syndrome) to reduce insulin problems and possibly improve fertility. (Fulghesu, et al, 2002)

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.

Possible toxicity
Researchers at the University of Virginia recently reported that acetylcysteine, which is found in many bodybuilding supplements, could potentially cause damage to the heart and lungs (Palmer et al., 2007). 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 (2007) was dramatically higher than that used in humans; nonetheless, the drug's effects on the hypoxic ventilatory response have been observed previously in human subjects at more moderate doses (Hildebrandt et al., 2002).

Additional Resources

 * 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
 * Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. 1998 Jun;31(6):710–5. PMID 9624310
 * 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
 * Dawson AH, Henry DA, McEwen J. Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust. 1989 Mar 20;150(6):329–31. PMID 2716644
 * Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, Lanzone A. "N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome." Fertility and Sterility 2002 Jun;77(6):1128-35. PMID 12057717
 * Hildebrandt W, Alexander S, Bärtsch P, Dröge W. "Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O(2) chemosensitivity." Blood 2002 Mar 1;99(5):1552-5. Accessed November 12, 2007. PMID 11861267
 * 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.
 * Kanter MZ. "Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning." Am J Health Syst Pharm 2006;63(19):1821–7. PMID 16990628.
 * Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, Fan K, Lee CH, Lam WF. "Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial." Journal of the American Medical Association 2003 Feb 5;289(5):553-8. Accessed December 12, 2007. PMID 12578487
 * 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
 * LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, Brady K, Kalivas PW, Malcolm R. "Is cocaine desire reduced by N-acetylcysteine?" Am J Psychiatry. 2007 Jul;164(7):1115-7. PMID 17606664
 * Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs. 2004 Jan;12(1):10–5. PMID 14700565
 * Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. "An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study." Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):389-94. PMID 17113207
 * Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL. "N-acetylcysteine and contrast-induced nephropathy in primary angioplasty." N Engl J Med. 2006 Jun 29;354(26):2773-82. PMID 16807414
 * 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.
 * Palmer LA, Doctor A, Chhabra P, Sheram ML, Laubach VE, Karlinsey MZ, Forbes MS, Macdonald T, Gaston B. "S-nitrosothiols signal hypoxia-mimetic vascular pathology." Journal of Clinical Investigation 2007 Sep;117(9): 2592-601. Accessed December 12, 2007. PMID 17786245
 * 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.
 * Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol. 2001 Jan;51(1):87–91. PMID 11167669
 * 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.
 * Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB, Herzenberg LA. "High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis." Proc Natl Acad Sci USA. 2006 Mar 21;103(12):4628-33. PMID 16537378
 * 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