Description

Acetylcysteine, or N-acetylcysteine, commonly abbreviated as NAC, is the N-acetyl derivative of the protein amino acid L-cysteine (see L-Cysteine). NAC is available as a nutritional supplement and as a drug. It is given orally or by slow intravenous infusion in the treatment of acetaminophen (known as paracetamol in Europe) overdose. NAC is also used in the treatment of respiratory disorders, such as acute and chronic bronchitis associated with the production of excessive or viscous mucus. For such respiratory disorders, it is delivered as an inhalant.

NAC is a delivery form of L-cysteine. L-cysteine is hygroscopic and slowly decomposes and oxidizes. NAC is more stable than L-cysteine, and it may be better absorbed. NAC, in addition to being known as N-acetylcysteine, is known as acetylcysteine and N-acetyl-L-cysteine. It is represented by the following chemical structure:

Chemical Structure

N-acetyl-L-cysteine

Actions & Pharmacology

Actions

NAC is a reducing agent and has antioxidant activity. It is also a mucolytic and a hepatoprotectant, and it may have anti-apoptotic activity.

Mechanism of Action

NAC's efficacy in the treatment of acetaminophen overdose is due mainly to its ability to regenerate liver stores of glutathione. NAC is a delivery form of L-cysteine, which serves as a major precursor to the antioxidant glutathione. An overdose of acetaminophen leads to its metabolism to large quantities of N-acetyl-benzoquinoneimine or NABQI in the liver. NABQI depletes hepatic glutathione stores, placing an enormous oxidative stress on the liver, which can lead to hepatic failure and be life-threatening.

NAC's mucolytic activity is believed to be due to its ability to reduce disulfide bonds in mucoproteins found in mucus, liquefying this viscous substance.

The hepatoprotectant activity of NAC is also due to its ability to serve as a precursor to glutathione. A major role of glutathione is the maintenance of a normal redox state of the liver. A normal redox state is vital to normal hepatic function.

There is some evidence that NAC may have anti-apoptotic activity, particularly in pancreatic beta-cells and nerve cells. This research is still preliminary, but it is believed that the possible anti-apoptotic effect of NAC is due to its antioxidant activity. Specifically, it is thought that NAC, in its role as a precursor to L-cysteine and glutathione, may protect cell membranes against lipid peroxidation and protein oxidation.

Pharmacokinetics

NAC is rapidly absorbed from the gastrointestinal tract and transported to the liver via the portal circulation, where it undergoes extensive first-pass metabolism. Peak plasma concentrations are observed approximately 0.5 to 1 hour following oral administration of doses of 200 to 600 milligrams. NAC is metabolized to N-acetylcysteine, N,N′-diacetylcysteine, N, N-diacetylcystine and L-cysteine, among other metabolites. L-cysteine itself is metabolized to glutathione, protein, taurine and sulfate. NAC has low bioavailability, probably because of its extensive first-pass metabolism in the liver. The terminal half-life of total NAC is approximately 6.25 hours after ingestion.

Indications & Usage

Broad claims are made for NAC. There is some support for claims that it is hepatoprotective, that it is of benefit in some with early adult respiratory distress syndrome and chronic obstructive pulmonary disease and that it might help protect against cardiovascular disease. There is also some preliminary suggestion that it might have some usefulness in the treatment of diabetes, some cancers and some immune disorders. A recent study suggests that NAC might have some favorable impact on age-related memory loss. Its benefit in reversing tolerance to nitrates in patients with coronary artery disease remains controversial. However, NAC may benefit some individuals who have noise-induced hearing loss.

Overdosage

There are no reports of overdosage with oral, supplemental NAC. There are reports of overdosage when using intravenous NAC for treatment of acetaminophen poisoning. Symptoms of overdosage are similar to those of anaphylaxis (rash, pruritis, flushing, nausea, vomiting, angioedema, tachycardia, bronchospasm, hypotension, hypertension, ECG abnormalities) but have been more severe. Hypotension appears to be a major symptom of overdosage. Other symptoms include respiratory depression, hemolysis, DIC (disseminated intravascular coagulation) and renal failure. It is unclear whether some of these symptoms may have been due to acetaminophen poisoning. Death has occurred in three patients receiving an overdosage of NAC while being treated for acetaminophen poisoning. The role of NAC in these deaths was unclear in two of the patients.

Dosage

Use of NAC for mucus liquefaction in severe broncho-pulmonary disease or acetaminophen overdosage should be dosed according to instructions in the package insert.

Supplemental intake ranges from 600 milligrams once to three times daily. Those who supplement with NAC should drink 6 to 8 glasses of water daily in order to prevent cystine renal stones. Cystine renal stones are rare but do occur.

Literature

Research & Summary

High-dose NAC has been used successfully as an antidote for acetaminophen poisoning and Amanita phalloides intoxication. In one series of 11 patients with Amanita phalloides poisoning, a detoxifying regimen that included NAC produced successful recovery in all but one subject without need of liver transplantation. Fulminant hepatic failure induced by acetaminophen overdose has similarly been significantly ameliorated by NAC treatment. It is believed that NAC accomplishes these benefits by preventing hepatic necrosis through replenishment of glutathione and, possibly, through enhanced oxygen delivery and consumption.

Given that acetaminophen overdose is the most common cause of calls to poison control centers in the United States, NAC's contribution is quite significant in this context. It has been suggested that NAC might also be useful in some infectious liver disorders, such as hepatitis C. As of yet, there is no evidence of efficacy in those diseases.

Several studies have indicated that NAC might be helpful in treating chronic obstructive pulmonary disease (COPD). In an open, controlled multicenter study of 169 patients with moderate-to-severe COPD, subjects were randomized to receive standard treatment plus 600 milligrams of NAC once daily or standard therapy alone for a six-month period. Exacerbations of COPD were reduced 41% in the NAC-treated group, compared with the standard therapy-only group. There was also a significant reduction in number of sick days among the NAC-treated. Another study found benefit from NAC and rutin in protecting the lungs of patients, with early adult respiratory distress syndrome ARDS. However, not all with ARDS benefit from NAC.

NAC has improved myocardial contraction in an animal model of myocardial ischemia. It has also been shown to inhibit platelet aggregation; and it has lowered lipoprotein (a) levels to a degree not previously achieved by either drugs or diet, according to some researchers. Additionally, some recent clinical studies have demonstrated that intravenous infusion of NAC during thrombolysis is associated with decreased size of infarct and increased rescue of left ventricular function.

One group of researchers concluded: ""Short-and long-term studies indicated that also on patients with unstable angina pectoris and threat of infarct, the intravenous or oral administration of N-acetylcysteine in association with nitroglycerin is highly effective in decreasing the risk of worsening, mainly by preventing the occurrence of acute myocardial infarction.''

Animal model work has produced preliminary evidence that NAC, apparently more than either vitamins C or E, or both, can be of some benefit in insulin-dependent diabetes mellitus. NAC reportedly inhibits pancreatic beta-cell apoptosis without affecting the rate of beta-cell proliferation. NAC has also been shown to moderately decrease blood glucose levels and to retain glucose-stimulated insulin secretion.

There is some interest in NAC as a possible anti-cancer agent. There is some preliminary work indicating that it might be helpful in the early stages of some cancers. It is hypothesized to be a logical chemopreventive agent in some cancers based on its properties and some experimental data demonstrating, among other things, extracellular inhibition of mutagenic agents, protection of DNA and nuclear enzymes, and dampening of reactive oxygen species.

One group of researchers, however, claims to have found some evidence of NAC-induced DNA damage in a human leukemia cell line and has cautioned that NAC ""may have the dual function of carcinogenic and anti-carcinogenic potentials.'' More research is needed.

NAC's therapeutic role, if any, in the treatment of immune disorders is similarly undecided. NAC has been shown to inhibit factors that are believed to stimulate HIV; this inhibition has been attributed to NAC-induced increases in intracellular thiol levels. These in vitro findings have not yet been demonstrated in clinical trials.

Recently, NAC was administered to eight patients with steroid-resistant acute graft-versus-host disease. Prompt significant response was seen in six of these subjects, four complete and two partial responses. More studies are needed.

A recent study of aged mice found some evidence that NAC can help prevent apoptotic death of neuronal cells and help protect against oxidative damage in synaptic mitochondria. NAC-supplemented mice were compared with unsupplemented mice fed standard food pellets. After 23 weeks, there was significant correction of some memory deficits in the aged mice receiving NAC, compared with those on the standard diet. And there were significant reductions in lipid peroxide and protein carbonyl levels in the synaptic mitochondria of the NAC-supplemented mice.

While some studies suggest that NAC can reverse tolerance to nitrates in patients with coronary artery disease, other studies have failed to demonstrate any benefit. On the other hand, NAC might help prevent/ameliorate noise-induced hearing loss, which is a growing problem; it is estimated that 600 million people worldwide are exposed to noise hazards occupationally, including 50 million in the United States. NAC has shown benefit in some, but not all, animal models of acute acoustic trauma. The military is reportedly investigating the use of NAC as a possible treatment agent to be administered shortly after acute acoustic trauma. Some preliminary clinical trials (typically using 900 mg of NAC, sometimes prior to exposure to loud noise such as occurs in a discotheque or on a shooting range) have produced mildly promising but inconclusive results. The rationale for trying NAC in this context relates to its antioxidant and cell-death inhibiting properties, experimentally found to be useful in protecting against noise-induced cochlear injury. More-rigorous trials are needed and warranted.

Contraindications, Precautions & Adverse Reactions

Contraindications

Known hypersensitivity to an NAC-containing product.

Precautions

Supplemental NAC should be avoided by nursing mothers and should only be used by pregnant women if prescribed by a physician.

N-acetylcysteine clearance is reduced in those with chronic liver disease as well as in pre-term newborns.

NAC may be harmful if administered early in the treatment of critically ill patients.

NAC may intensify headaches in those taking nitrates for the treatment of angina.

Although the incidence of cystine renal stones is low, they do occur. Those who do form renal stones, particularly cystine stones, should avoid NAC supplements.

NAC and its sulfhydryl metabolites, like other sulfhydryl-containing substances, could produce a false-positive result in the nitroprusside test for ketone bodies used in diabetes.

NAC should be used with caution in those with a history of peptic ulcer disease, since mucolytic agents may disrupt the gastric mucosal barrier.

Adverse Reactions

Adverse reactions reported with oral NAC include nausea, vomiting, diarrhea, headache (especially when used along with nitrates) and rashes. There are rare reports of renal stone formation.

Adverse reactions reported with intravenous NAC include bronchospasm, nausea, vomiting, stomatitis, rhinorrhea, headache, tinnitus, urticaria, rashes, chills and fever. There are rare reports of anaphylactic reactions. The most common symptoms of those experiencing anaphylactoid reactions are rash, pruritus, flushing, nausea, vomiting, angioedema, tachycardia, bronchospasm, hypotension, hypertension and ECG change. The anaphylactoid reactions are pseudo-allergic rather than immunologic.

Interactions

Nitrates: Use of supplemental NAC along with nitrates may cause headaches.

Carbamazepine: Use of supplemental NAC along with carbamazepine may cause reduced serum levels of carbamazepine.

No interactions with nutritional supplements, food or herbs are known.