N-Acetylcysteine: Multiple Clinical Applications



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N-acetylcysteine is the acetylated variant of the amino acid L-cysteine and is widely used as the specific antidote for acetaminophen overdose. Other applications for N-acetylcysteine supplementation supported by scientific evidence include prevention of chronic obstructive pulmonary disease exacerbation, prevention of contrast-induced kidney damage during imaging procedures, attenuation of illness from the influenza virus when started before infection, treatment of pulmonary fibrosis, and treatment of infertility in patients with clomiphene-resistant polycystic ovary syndrome. Preliminary studies suggest that N-acetylcysteine may also have a role as a cancer chemopreventive, an adjunct in the eradication of Helicobacter pylori, and prophylaxis of gentamicin-induced hearing loss in patients on renal dialysis.

Although N-acetylcysteine is widely known as an antidote to acetaminophen overdose,1 it has multiple other uses supported by varying levels of evidence. These clinical applications stem from its ability to support the body's antioxidant and nitric oxide systems during stress, infections, toxic assault, and inflammatory conditions. Supplementation with N-acetylcysteine has been shown to increase levels of glutathione, the body's major anti-oxidant.2 Glutathione is critically important for detoxifying an array of toxic substances, including xenobiotics (chemicals foreign to biologic systems), peroxide compounds, and other free radical–generating molecules. It thereby exerts a profound protective effect on cells.3

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Uses of N -acetylcysteine Evidence rating References

Preservation of lung function in COPD

C

6

Prevention of exacerbation of COPD

B

5, 7

Prevention of contrast-induced nephropathy

B

16

Attenuation of influenza illness

B

18

Preservation of lung function in idiopathic pulmonary fibrosis

C

19

Treatment of infertility in women with clomiphene (Clomid)-resistant polycystic ovary syndrome

B

20, 21


COPD = chronic obstructive pulmonary disease.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Uses of N -acetylcysteine Evidence rating References

Preservation of lung function in COPD

C

6

Prevention of exacerbation of COPD

B

5, 7

Prevention of contrast-induced nephropathy

B

16

Attenuation of influenza illness

B

18

Preservation of lung function in idiopathic pulmonary fibrosis

C

19

Treatment of infertility in women with clomiphene (Clomid)-resistant polycystic ovary syndrome

B

20, 21


COPD = chronic obstructive pulmonary disease.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Of glutathione's three component amino acids (i.e., glutamate, glycine, and cysteine), cysteine has the lowest intracellular concentration.3 Because de novo synthesis is the primary mechanism by which glutathione is replenished, cysteine availability can limit the rate of glutathione synthesis during times of oxidative stress.2 By correcting or preventing glutathione depletion, N-acetylcysteine may ameliorate the inflammation that occurs in conditions such as chronic obstructive pulmonary disease (COPD), influenza, and idiopathic pulmonary fibrosis. In addition to its antioxidant action, N-acetylcysteine acts as a vasodilator by facilitating the production and action of nitric oxide. This property is an important mechanism of action in the prophylaxis of contrast-induced nephropathy and the potentiation of nitrate-induced vasodilation.4

COPD

N-acetylcysteine has been shown to have a positive effect on the clinical course of COPD.2 An open-label study of 1,392 patients found that N-acetylcysteine reduced the viscosity of expectorated phlegm, reduced cough severity, and improved ease of expectoration in 80, 74, and 71 percent of patients, respectively, after two months of treatment.5 The study also reported “marked improvements” in rhonchi, crepitations, dyspnea, cyanosis, and associated heart failure after one to two months of therapy.5 In another large, open-label trial that compared N-acetylcysteine with a control medication, patients taking N-acetylcysteine experienced a decrease in the deterioration of lung function as measured by forced expiratory volume in one second (FEV1).6 This effect was most pronounced in patients older than 50 years. In this subgroup, the annual decline in lung function was almost 50 percent less in those taking N-acetylcysteine (an annual decrease of FEV1 of 30 mL versus 54 mL in the control group).6

N-acetylcysteine has also been studied for its ability to prevent exacerbation of COPD. A meta-analysis of 11 double-blind, placebo-controlled trials, selected on the basis of quality criteria from 39 available studies, revealed a statistically significant difference between the number of exacerbations in patients treated with N-acetylcysteine and those receiving placebo.7 Combined, these trials included 2,011 analyzable patients—996 who received N-acetylcysteine and 1,015 who received placebo. The number needed to treat for one patient to avoid an exacerbation was 5.8. Small improvements in FEV1 were also reported. The rate of adverse effects, most commonly gastrointestinal, was similar to or slightly lower than that of placebo, with a number needed to harm of 198.7

One prominent study did not show any effect of N-acetylcysteine on primary end points.8 A total of 523 patients with COPD were randomized to receive 600 mg of N-acetylcysteine per day or placebo and were followed for three years. Although the primary end points of exacerbation rate and deterioration of FEV1 were not notably different between the groups, functional residual capacity did improve in the N-acetylcysteine group, and the exacerbation rate was much improved in patients not taking inhaled steroids.8

Contrast-Induced Nephropathy

Approximately 10 million procedures using radiologic contrast material are done in the United States annually.9 The occurrence of contrast-induced nephropathy ranges from approximately 2 percent in patients with creatinine levels below 1.5 mg per dL (130 μmol per L) to 20 percent in patients with levels above 2.5 mg per dL (220 μmol per L). Patients with diabetes and all patients with creatinine levels higher than 2.0 mg per dL (180 μmol per L) are at high risk.10 Contrast-induced nephropathy is also associated with dramatically increased mortality and morbidity that persists after hospital discharge, regardless of the need for renal dialysis.10

In 2000, a positive trial using N-acetylcysteine as prophylaxis for contrast-induced nephropathy was published in a high-profile journal,11 initiating a burst of research activity that to date has resulted in more than 20 randomized controlled trials (RCTs) and 13 meta-analyses.1215 Seven of the meta-analyses determined that N-acetylcysteine is beneficial for preventing contrast-induced nephropathy, five determined that the data are inconclusive, and one determined that N-acetylcysteine is ineffective in preventing renal dialysis.1215 Although meta-analyses are considered the gold standard for evidence in clinical medicine, the RCTs for contrast-induced nephropathy available to date are heterogeneous clinically (i.e., differences in study design, patient populations, intervention protocols, and primary outcomes) and statistically (i.e., variation in the trial results is higher than expected by chance alone), limiting the conclusions that can be drawn from them.15

One recent trial studied 354 patients undergoing primary angioplasty for acute myocardial infarction.16 Patients were randomized to placebo, standard-dose N-acetylcysteine (600-mg bolus intravenously before angioplasty, followed by 600 mg orally twice daily for four days), or to double-dose N-acetylcysteine (1,200-mg bolus intravenously, followed by 1,200 mg orally twice daily for four days). Patients in the N-acetylcysteine groups had marked dose-dependent reductions of contrast-induced nephropathy (35 percent in the control group, 15 percent in the standard-dose N-acetylcysteine group, and 8 percent in the high-dose N-acetylcysteine group [ P < .0001]). In addition, in-hospital mortality was markedly reduced by N-acetylcysteine (P = .03), as was the combined end point of death, acute renal failure requiring dialysis, and the need for mechanical ventilation during the acute phase of myocardial infarction (P = .002).16  This protocol (Table 116) is the only one to date showing a mortality benefit.

Table 1

One Protocol for Preventing Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography and Angioplasty

Dosing

Before the procedure, administer a 1,200-mg intravenous bolus of N-acetylcysteine

After the procedure, administer a 1,200-mg oral dose of N-acetylcysteine twice daily for 48 hours

Hydration

After the procedure, administer 1 mL of normal saline per kg per hour for 12 hours (reduced to 0.5 mL per hour in cases of overt heart failure)


Information from reference 16.

Table 1   One Protocol for Preventing Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography and Angioplasty

View Table

Table 1

One Protocol for Preventing Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography and Angioplasty

Dosing

Before the procedure, administer a 1,200-mg intravenous bolus of N-acetylcysteine

After the procedure, administer a 1,200-mg oral dose of N-acetylcysteine twice daily for 48 hours

Hydration

After the procedure, administer 1 mL of normal saline per kg per hour for 12 hours (reduced to 0.5 mL per hour in cases of overt heart failure)


Information from reference 16.

Because of the dichotomous research findings, prophylaxis of contrast-induced nephropathy with N-acetylcysteine is not considered standard care. Nevertheless, use of N-acetylcysteine has increased based on its demonstrated safety and the potential effectiveness of specific protocols.17

Influenza

Compared with placebo, N-acetylcysteine dramatically attenuated influenza illness in a population of frail older adults who participated in a double-blind randomized placebo-controlled study over a six-month period.18 The 262 participants were randomized to receive either N-acetylcysteine in a dosage of 600 mg twice daily or placebo, beginning before and continuing through the 1991 to 1992 influenza season. Although both groups had similar rates of seroconversion to A/H1N1 Singapore 6/86 virus, patients taking N-acetylcysteine were much less likely to have clinical influenza illness (29 percent of the N-acetylcysteine group versus 51 percent of the placebo group; P = .0006). In addition, episodes of clinical influenza illness that occurred in N-acetylcysteine-treated patients were, on average, much less severe. Cell-mediated immunity continually improved in the N-acetylcysteine group as a whole, whereas immunity in the placebo group remained unchanged.18

Idiopathic Pulmonary Fibrosis

In a study of 155 patients with idiopathic interstitial pulmonary fibrosis randomized to N-acetylcysteine (600 mg three times daily) or placebo, those receiving N-acetylcysteine showed notably less deterioration in lung function over one year, as measured by vital capacity and single-breath carbon monoxide–diffusing capacity (a decrease of 9 versus 24 percent; P = .02).19 In addition, those patients receiving N-acetylcysteine had fewer adverse effects caused by bone marrow toxicity from the azathioprine (Imuran) that both groups received as part of standard care (4 versus 13 percent; P = .03).19

Polycystic Ovary Syndrome

N-acetylcysteine may ameliorate insulin resistance. In a double-blind RCT, 1,200 mg of N-acetylcysteine or placebo was added to the clomiphene (Clomid) regimen of women with polycystic ovary syndrome and clomiphene-resistant infertility.20 In the group receiving N-acetylcysteine, clinically and statistically significant increases in both ovulation and pregnancy occurred.20 These results have been replicated in a subsequent trial.21

Other Indications

N-acetylcysteine may play a role in preventing post-surgical complications. One study on the prevention of acute renal failure after cardiac surgery showed a trend in favor of patients treated with N-acetylcysteine that did not reach statistical significance (P = .06), whereas subgroup analysis of the patients placed on cardiopulmonary bypass (90 percent of the sample) revealed that those treated with N-acetylcysteine had a marked reduction in acute renal failure (P = .03).22 Another small study of 22 patients revealed that N-acetylcysteine may be useful in preventing pulmonary complications in patients undergoing esophagectomy for cancer.23

N-acetylcysteine may also suppress colon polyps,24 and has an additive effect when used as an adjunct to standard therapy in the eradication of Helicobacter pylori.25 In addition, a small study found that N-acetylcysteine may decrease the risk of ototoxicity in patients on hemodialysis who are receiving gentamicin.26

Adverse Reactions and Drug Interactions

At dosages of 1,200 mg twice daily or lower, N-acetylcysteine is well tolerated. At these dosages, side effects are unusual, but may include nausea, vomiting, diarrhea, transient skin rash, flushing, epigastric pain, and constipation.27 At the much larger dosages used to treat acetaminophen overdose, N-acetylcysteine is often poorly tolerated, with side effects such as headache, tinnitus, urticaria, rash, chills, fever, and anaphylactoid reactions (pseudoanaphylaxis).27 N-acetylcysteine strongly potentiates the effect of nitroglycerin and related medications, and caution should be used in patients receiving these agents in whom it may cause hypotension.4

How Supplied

As an over-the-counter supplement, N-acetylcysteine is available in 500- to 1,000-mg capsules. The strength most commonly available is the 600-mg capsule (Pure Encapsulations). In addition, an intravenous preparation (Acetadote) to treat acetaminophen overdose is available.28 Select brands of N-acetylcysteine are listed in Table 2.

Table 2

Select Brands of N-Acetylcysteine

Brand Strength Formulation

Pure Encapsulations (on request, provides assay results from a third-party independent laboratory)

Available in 600 mg and 900 mg

Capsule

Acetadote

200 mg per mL

Solution for intravenous administration

Table 2   Select Brands of N-Acetylcysteine

View Table

Table 2

Select Brands of N-Acetylcysteine

Brand Strength Formulation

Pure Encapsulations (on request, provides assay results from a third-party independent laboratory)

Available in 600 mg and 900 mg

Capsule

Acetadote

200 mg per mL

Solution for intravenous administration

Bottom Line

N-acetylcysteine is a safe, inexpensive, and well-tolerated antioxidant with a well-defined mechanism of action. Because of the highly favorable risk/benefit ratio and the low rate of adverse events, physicians might consider use of N-acetylcysteine in select patients to diminish exacerbation of COPD symptoms; reduce the risk of contrast-induced nephropathy; attenuate influenza illness; decrease the rate of deterioration of pulmonary function in idiopathic pulmonary fibrosis; and serve as an adjunct to clomiphene in the treatment of infertility in women with polycystic ovalyceury syndrome. Key points about N-acetylcysteine are summarized in Table 3.1,4,5,7,8,16,1821

Table 3

Key Points About N-Acetylcysteine

Effectiveness

Widely used as antidote for acetaminophen overdose1

Prevention of exacerbation of COPD; solid evidence from multiple RCTs and meta-analyses5,7,8

Prevention of contrast-induced nephropathy; conflicting evidence, but better quality RCTs appear to show definite benefit16

Attenuation and prevention of influenza illness in frail older adults; good evidence from a single well-done RCT18

Decreased rate of lung function deterioration in idiopathic pulmonary fibrosis; good evidence from a single well-done RCT19

Increased rates of ovulation and pregnancy when given with clomiphene (Clomid) in PCOS; solid evidence from two well-done RCTs20,21

Adverse effects

Rare at dosages of 1,200 mg twice daily or less; mostly gastrointestinal

Interactions

Caution in patients taking nitroglycerin and related medications because of potentiation of vasodilatory action4

Dosages

Prophylaxis against COPD exacerbation: 600 mg to 1,200 mg daily in divided doses7,8

Prevention of contrast-induced nephropathy in patients with coronary angioplasty (Table 1)16

Attenuation of influenza illness: 600 mg twice daily before and throughout influenza season18

Decreased deterioration of lung function in idiopathic pulmonary fibrosis: 1,800 mg in divided doses19

Adjunct to clomiphene in PCOS: 1,200 mg per day in divided doses20,21

Cost*

$12 to $15 per month, depending on brand and dosage

Bottom line

Safe and inexpensive supplement


COPD = chronic obstructive pulmonary disease; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial.

*— Estimated retail price of one month's treatment based on information obtained at www.drugstore.com (accessed March 10, 2009).

Information from references 1, 4, 5, 7, 8, 16, and 18 through 21.

Table 3   Key Points About N-Acetylcysteine

View Table

Table 3

Key Points About N-Acetylcysteine

Effectiveness

Widely used as antidote for acetaminophen overdose1

Prevention of exacerbation of COPD; solid evidence from multiple RCTs and meta-analyses5,7,8

Prevention of contrast-induced nephropathy; conflicting evidence, but better quality RCTs appear to show definite benefit16

Attenuation and prevention of influenza illness in frail older adults; good evidence from a single well-done RCT18

Decreased rate of lung function deterioration in idiopathic pulmonary fibrosis; good evidence from a single well-done RCT19

Increased rates of ovulation and pregnancy when given with clomiphene (Clomid) in PCOS; solid evidence from two well-done RCTs20,21

Adverse effects

Rare at dosages of 1,200 mg twice daily or less; mostly gastrointestinal

Interactions

Caution in patients taking nitroglycerin and related medications because of potentiation of vasodilatory action4

Dosages

Prophylaxis against COPD exacerbation: 600 mg to 1,200 mg daily in divided doses7,8

Prevention of contrast-induced nephropathy in patients with coronary angioplasty (Table 1)16

Attenuation of influenza illness: 600 mg twice daily before and throughout influenza season18

Decreased deterioration of lung function in idiopathic pulmonary fibrosis: 1,800 mg in divided doses19

Adjunct to clomiphene in PCOS: 1,200 mg per day in divided doses20,21

Cost*

$12 to $15 per month, depending on brand and dosage

Bottom line

Safe and inexpensive supplement


COPD = chronic obstructive pulmonary disease; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial.

*— Estimated retail price of one month's treatment based on information obtained at www.drugstore.com (accessed March 10, 2009).

Information from references 1, 4, 5, 7, 8, 16, and 18 through 21.

The Author

PAUL J. MILLEA, MD, MA, FAAMA, is a family physician in the Department of Integrative Medicine at Mid-Atlantic Permanente Medical Group, P.C., in Falls Church, Va.

Address correspondence to Paul J. Millea, MD, MA, Mid-Atlantic Permanente Medical Group, P.C., 201 N. Washington St., Falls Church, VA 22046 (e-mail: paulmillea@gmail.com). Reprints are not available from the author.

Author disclosure: Nothing to disclose.

REFERENCES

1. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2006;(2):CD003328.

2. Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J. 2004;23(4):629–636.

3. Dickinson DA, Moellering DR, Iles KE, et al. Cytoprotection against oxidative stress and the regulation of glutathione synthesis. Biol Chem. 2003;384(4):527–537.

4. Ardissino D, Merlini PA, Savonitto S, et al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol. 1997;29(5):941–947.

5. Tattersall AB, Bridgman KM, Huitson A. Acetylcysteine (Fabrol) in chronic bronchitis—a study in general practice. J Int Med Res. 1983;11(5):279–284.

6. Lundbäck B, Lindström M, Andersson S, Nyström L, Rosenhall L, Stjernberg N. Possible effect of acetylcysteine on lung function. Eur Respir J. 1992;5(suppl 15):289s.

7. Stey C, Steurer J, Bachmann S, Medici TC, Tramèr MR. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J. 2000;16(2):253–262.

8. Decramer M, Ruttenvan Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial [published correction appears in Lancet. 2005;366(9490):984]. Lancet. 2005;365(9470):1552–1560.

9. Liu R, Nair D, Ix J, Moore DH, Bent S. N-acetylcysteine for the prevention of contrast-induced nephropathy. A systematic review and meta-analysis. J Gen Intern Med. 2005;20(2):193–200.

10. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002;105(19):2259–2264.

11. 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(3):180–184.

12. Bagshaw SM, McAlister FA, Manns BJ, Ghali WA. Acetylcysteine in the prevention of contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med. 2006;166(2):161–166.

13. Zagler A, Azadpour M, Mercado C, Hennekens CH. N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials. Am Heart J. 2006;151(1):140–145.

14. Seyon RA, Jensen LA, Ferguson IA, Williams RG. Efficacy of N-acetyl-cysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention. Heart Lung. 2007;36(3):195–204.

15. Gonzales DA, Norsworthy KJ, Kern SJ, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007;5:32.

16. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006;354(26):2773–2782.

17. Van Praet JT, De Vriese AS. Prevention of contrast-induced nephropathy: a critical review. Curr Opin Nephrol Hypertens. 2007;16(4):336–347.

18. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10(7):1535–1541.

19. Demedts M, Behr J, Buhl R, et al., for the IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229–2242.

20. Rizk AY, Bedaiwy MA, Al-Inany HG. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome. Fertil Steril. 2005;83(2):367–370.

21. Badawy A, State O, Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a crossover trial. Acta Obstet Gynecol Scand. 2007;86(2):218–222.

22. Sisillo E, Ceriani R, Bortone F, et al. N-acetylcysteine for prevention of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery: a prospective, randomized, clinical trial. Crit Care Med. 2008;36(1):81–86.

23. Zingg U, Hofer CK, Seifert B, Metzger U, Zollinger A. High dose N-acetylcysteine to prevent pulmonary complications in partial or total transthoracic esophagectomy: results of a prospective observational study. Dis Esophagus. 2007;20(5):399–405.

24. Estensen RD, Levy M, Klopp SJ, et al. N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps. Cancer Lett. 1999;147(1–2):109–114.

25. Gurbuz AK, Ozel AM, Ozturk R, Yildirim S, Yazgan Y, Demirturk L. Effect of N-acetyl cysteine on Helicobacter pylori. South Med J. 2005;98(11):1095–1097.

26. Feldman L, Efrati S, Eviatar E, et al. Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int. 2007;72(3):359–363.

27. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007;7(4):355–359.

28. Hendler SS, ed. PDR for Nutritional Supplements. 1st ed. Montvale, N.J.: Medical Economics; 2001:11–14.



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