N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex)

Indications

Inhaled

Cystic Fibrosis (CF) (see Cystic Fibrosis, [[Cystic Fibrosis]])

  • Pharmacology: mucolytic

Oral

Acetaminophen Intoxication (see Acetaminophen, [[Acetaminophen]])

  • xxx

Acute on Chronic Liver Failure (see End-Stage Liver Disease, [[End-Stage Liver Disease]])

  • xxx

Prophylaxis Against Chronic Obstructive Pulmonary Disease (COPD) Exacerbation (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])

  • Cochrane Database Systematic Review of Mucolytic Effect on COPD Exacerbation Rate (2012) [MEDLINE]
    • Main Findings: in chronic bronchitis or COPD, mucolytics may produce a small decrease in acute exacerbations, but have little or no effect on the overall quality of life (the effect on COPD exacerbation rate demonstrated in early trials was larger than that found in the more recent studies, possibly due to these earlier smaller trials having higher risk of selection or publication bias)
  • PANTHEON N-Acetylcysteine Trial (2014) [MEDLINE]
    • Study: prospective, randomized, double-blind, placebo-controlled trial of N-Acetylcysteine (see N-Acetylcysteine, [[N-Acetylcysteine]]) performed in China, n = 1006 -> primary endpoint was the annual COPD exacerbation rate
    • Main Findings: in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg PO BID decreases the number of exacerbations (especially in disease of moderate severity)
    • Conclusions: probably exerts its effect via a mucolytic action: N-acetylcysteine cleaves disulfide bonds which cross-link glycoproteins in mucus -> results in decreased mucus viscosity, facilitating airway mucus clearance
      • Other potential mechanisms, such as inhibition of generation or neutralization of reactive species (with a potential anti-inflammatory effect), are less supported by the available data

Prophylaxis Against Constrast-Induced Nephropathy (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • xxx

Intravenous

Acetaminophen Intoxication (see Acetaminophen, [[Acetaminophen]])

  • xxx

Pharmacology

  • Mucolytic Action (Inhaled Mucolytic): free sulfhydryl group in N-acetylcysteine opens up the disulfide bonds in mucoproteins -> decreases mucous viscosity
  • Protection Against Contrast-Induced Nephropathy (Oral Use Prior to Contrast Administration): scavenging of oxygen-derived radicals and improvement of endothelium-dependent vasodilation
  • Restoration of Hepatic Glutathione, Serving as a Glutathione Substitute, and Enhancing the Non-Toxic Sulfate Conjugation of Acetaminophen (Oral/Intravenous Use in Acetaminophen Intoxication)

Metabolism

  • Renal Excretion

Administration

Inhaled

  • General Comments
    • Onset of Action: 5-10 min
    • Duration of Action: >1 hr
  • Regimen
    • Premedicate with Prophylactic Bronchodilator
    • 10% Solution Nebulized: 6-10 mL q6hrs (or 20% Solution Nebulized: 3-5 mL q6hrs)

Oral (Mucomyst)

  • Time to Peak Plasma Level: 1-2 hrs
  • FDA-Approved 72 hr Regimen: total dose = 1330 mg/kg
    • Loading Dose: 140 mg/kg
    • Maintenance Dose: 70 mg/kg q4hrs x 17 doses (repeat dose if emesis occurs within 1 hr of administration)
    • Indications for Extension of N-Acetylcysteine Treatment Course
      • Concomitant ingestion of other substances
      • Persistently elevated acetaminophen level after 72 hr regimen
      • Persistently elevated INR after 72 hr regimen
      • Persistently elevated liver function tests after 72 hr regimen
      • Pre-existing liver disease
      • Suspected massive acetaminophen overdose
  • Dose Adjustment
    • Hepatic: none required
    • Renal: none required

Intravenous (Acetadote)

  • FDA-Approved 21 hr Regimen: total dose = 300 mg/kg
    • Loading Dose: 150 mg/kg (Max: 15 g) over 1 hr
    • Second Dose: 50 mg/kg (Max: 5 g) over 4 hrs
    • Third Dose: 100 mg/kg (Max: 10 g) over 16 hrs
    • Indications for Extension of N-Acetylcysteine Treatment Course
      • Concomitant ingestion of other substances
      • Persistently elevated acetaminophen level after 21 hr regimen
      • Persistently elevated INR after 21 hr regimen
      • Persistently elevated liver function tests after 21 hr regimen
      • Pre-existing liver disease
      • Suspected massive acetaminophen overdose
  • Dose Adjustment
    • Hepatic: none required
    • Renal: none required
    • Obesity (>100 kg)
      • Loading Dose: 15 g over 1 hr
      • Second Dose: 5 g over 4 hrs
      • Third Dose: 10 g over 16 hrs

Adverse Effects

Allergic/Immunologic Adverse Effects

Anaphylactoid Reaction (see Anaphylaxis, [[Anaphylaxis]])

  • Epidemiology
    • Intravenous Administration: occurs in 8-18% of cases
    • Oral Administration: unknown incidence
  • Factors Which Increase Risk of Anaphylactoid Reactions
    • History of bronchospasm
    • Shorter infusion periods
  • Factors Which Decrease Risk of Anaphylactoid Reactions
    • High acetaminophen level (>150 mg/L)
  • Clinical: usually occurs within 30-60 min
  • Treatment
    • May resolve spontaneously in some cases
    • Stop Infusion and Treat Anaphylactoid Reaction: then cautiously restart infusion

Angioedema (see Angioedema, [[Angioedema]])

  • Epidemiology
    • Intravenous Administration: occurs in 6-8% of cases
    • Oral Administration: unknown incidence

Urticaria (see Urticaria, [[Urticaria]])

  • Epidemiology
    • Intravenous Administration: occurs in 6-8% of cases
    • Oral Administration: unknown incidence

Cardiovascular Adverse Effects

Hypotension (see Hypotension, [[Hypotension]])

  • Epidemiology
    • Oral Administration

Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])

  • Epidemiology
    • Intravenous Administration: occurs in 1-4% of cases
    • Oral Administration: unknown incidence

Dermatologic Adverse Effects

Flushing (see Flushing, [[Flushing]])

  • Epidemiology
    • Intravenous Administration: occurs in 1-8% of cases

Pruritus (see Pruritus, [[Pruritus]])

  • Epidemiology
    • Oral Administration: unknown incidence
    • Intravenous Administration: occurs in 1-4% of cases

Rash

  • Epidemiology
    • Intravenous Administration: occurs in 2-4% of cases

Gastrointestinal Adverse Effects

Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])

  • Epidemiology
    • Inhaled Administration: unknown incidence
    • Intravenous Administration: nausea occurs in 1-6% of cases, vomiting occurs 2-10% of cases
    • Oral Administration: unknown incidence

Pulmonary Adverse Effects

Bronchospasm (see Obstructive Lung Disease, [[Obstructive Lung Disease]])

  • Epidemiology
    • Inhaled Administration
    • Oral Administration

Other Adverse Effects

  • xxx
  • xxx
  • xxx

References

  • Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. 1998 Jun;31(6):710-5 [MEDLINE]
  • Adverse reactions associated with acetylcysteine. Clin Toxicol (Phila). 2009 Feb;47(2):81-8. doi: 10.1080/15563650802665587 [MEDLINE]
  • Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis. West J Emerg Med. 2013 May;14(3):218-26. doi: 10.5811/westjem.2012.4.6885 [MEDLINE]
  • Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose. Eur J Emerg Med. 2014 Feb;21(1):57-60. doi: 10.1097/MEJ.0b013e328364eb22 [MEDLINE]

Adverse reactions associated with acetylcysteine.
Abstract
INTRODUCTION:
Paracetamol (acetaminophen) is one of the most common agents deliberately ingested in self-poisoning episodes and a leading cause of acute liver failure in the western world. Acetylcysteine is widely acknowledged as the antidote of choice for paracetamol poisoning, but its use is not without risk. Adverse reactions, often leading to treatment delay, are frequently associated with both intravenous and oral acetylcysteine and are a common source of concern among treating physicians.
METHODS:
A systematic literature review investigating the incidence, clinical features, and mechanisms of adverse effects associated with acetylcysteine.
RESULTS:
A variety of adverse reactions to acetylcysteine have been described ranging from nausea to death, most of the latter due to incorrect dosing. The pattern of reactions differs with oral and intravenous dosing, but reported frequency is at least as high with oral as intravenous. The reactions to the intravenous preparation result in similar clinical features to true anaphylaxis, including rash, pruritus, angioedema, bronchospasm, and rarely hypotension, but are caused by nonimmunological mechanisms. The precise nature of this reaction remains unclear. Histamine now seems to be an important mediator of the response, and there is evidence of variability in patient susceptibility, with females, and those with a history of asthma or atopy are particularly susceptible. Quantity of paracetamol ingestion, measured through serum paracetamol concentration, is also important as higher paracetamol concentrations protect patients against anaphylactoid effects. Most anaphylactoid reactions occur at the start of acetylcysteine treatment when concentrations are highest. Acetylcysteine also affects clotting factor activity, and this affects the interpretation of minor disturbances in the International Normalized Ratio in the context of paracetamol overdose.
CONCLUSION:
This review discusses the incidence, clinical features, underlying pathophysiological mechanisms, and treatment of adverse reactions to acetylcysteine and identifies particular “at-risk” patient groups. Given the commonality of adverse reactions associated with acetylcysteine, it is important to ensure that any adverse event does not preclude patients from receiving maximal hepatic protection, particularly in the context of significant paracetamol ingestion. Further work on mechanisms should allow specific therapies to be developed.
PMID: 19280424 [PubMed – indexed for MEDLINE]Clin Toxicol (Phila). 2009 Feb;47(2):81-8. doi: 10.1080/15563650802665587.
Adverse reactions associated with acetylcysteine.

Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose.
Abstract
OBJECTIVE:
Adverse drug reactions (ADRs) to N-acetylcysteine (NAC) treatment for paracetamol overdose are typically anaphylactoid in origin and occur in 2-48% of treated patients. We explored the incidence and management of NAC ADR in our unit.
PATIENTS AND METHODS:
Case notes of patients who presented with paracetamol overdose and had ADR to NAC between February 2005 and June 2011 were reviewed. A total of 1648 patients presented with suspected paracetamol overdose and 660 received NAC treatment. Within this group, 82 patients had documented NAC-related ADR.
RESULTS:
ADR developed in 12.4% (82/660) of patients receiving intravenous NAC and 59 had full documentation available and were included in this study (34 women, 25 men). ADR occurred in the 15-min (150 mg/kg) bag in 36 cases (61%), 22 in the 4-h (50 mg/kg) bag (37%) and one in the 16-h (100 mg/kg) bag (2%). Symptoms were classified as minimal (n=16, 27%), moderate (n=26, 44%) and severe (n=17, 29%). Asthma and female sex, which are reported risk factors for ADR, did not lead to the development of more severe ADR (P=0.771 and 0.330, respectively). Treatments administered included stopping the NAC infusion (n=32, 54%), administration of antiemetics (n=36, 61%), H1 antihistamines (n=26, 44%), steroids (n=16, 27%), inhaled B2 agonists (n=6, 10%) and adrenaline (n=3, 5%).
CONCLUSION:
The incidence of ADR to NAC was comparable with published studies, although there was no association of severity with asthma or female sex. The management of ADRs is variable, with frequent, inappropriate use of steroids. Education about the pathophysiology of these ADRs may improve management.
PMID: 23912471 [PubMed – indexed for MEDLINE]
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Management of anaphylactoid reactions to intravenous N-acetylcysteine.
Abstract
STUDY OBJECTIVE:
To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction.
METHODS:
In phased 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center.
RESULTS:
In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and the antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphenhydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be started 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction.
CONCLUSION:
Non-life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine.

Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis.
Abstract
INTRODUCTION:
There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine.
METHODS:
Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment.
RESULTS:
We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.
CONCLUSION:
Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration.
Comment in
Is intravenous acetylcysteine more effective than oral administration for the prevention of hepatotoxicity in acetaminophen overdose? [Ann Emerg Med. 2014]
PMID: 23687539 [PubMed] PMCID: PMC3656701 Free PMC Article