N-acetylcysteine

Related FACEM curriculum (2022) learning objectives:

ME 3.8.1.6(e) Principles of management of toxicological presentations including: Indications for antidotes

#completed #carded

History

Benefits of GSH described quite soon after first reports of APAP hepatotoxicity
NAC first suggested as an antidote in 1974
IV and PO both found efficacious. In USA, PO approved 1985 and IV in 2004.
Previous studied (but not used) in
- An oncologic chemopreventive and antineoplastic
- Lung and cardiac injury
- MODS in sepsis and trauma
- COPD
- Post-cardiac surgery
- Prevention of nephrotoxicity due to ifosfamide
- Hepatorenal syndrome
- H. pylori infection
- Nectrotising entercolitis
- Sickle cell disease
- Bipolar affective disorder
- IV contrast-induced nephropathy (ineffective, or at best a very modest effect)

Pharmacology

Thiol-containing compound that ultimately increases glutathione (GSH)
- Increases intracellular cysteine
  - NAC deacetylates into cysteine
  - Also causes release of protein and membrane bound cysteine
- Cysteine, glycine and glutamate synthesise GSH
- Cysteamine, methionine and NAC are GSH substitutes/precursors
  - NAC is considered most effective and better tolerated
Highly effective (nearly 100% if started within 8 hours) antidote with three distinct roles in APAP (paracetamol) poisoning.
- Prevents toxicity by limiting NAPQI formation as a GSH precursor and detoxifying NAPQI as a GSH substitute
  - Supplies cysteine - thereby permitting saturable sulfation of APAP and preventing oxidation of APAP
  - Glutathione allows NAPQI to be conjugated with cysteine and mercaptate
- Treats toxicity through non-specific multiorgan protective mechanisms
  - May reverse NAPQI oxidation back to APAP
  - Reduces hepatocyte injury
  - Appeared to reduce the need for vasopressors and incident of cerebral oedema and death in fulminant liver failure
    - Appeared to be independent of degree of hepatotoxicity
  - Other hypothesised benefits:
    - Effect against reactive oxygen species
    - Improved oxygen delivery
    - Improved mitochondrial ATP production due to GSH supply
    - Preservation of cerebral perfusion in oedema
  - Effect of NAC on APAP-related AKI appears to limited
NAC should be continued until APAP metabolism is complete
- This is based on [APAP], [AST/ALT] and PT/INR levels
- Provides a basis for a truncated course of NAC, but results of a recent RCT are yet to be published (NACSTOP 2)
- Also provides a basis for extended NAC treatment protocols
Dose adjustment in massive APAP ingestions
- These patients rarely have prolonged or bimodal peaks in [APAP]
- Some question on whether traditional NAC protocols is sufficient
- But also limited data on benefit of higher doses
- See local guidelines
Weight based dosing with fixed volume of diluent may cause issues
- Large volume of solute-free water in children -> hypoNa
- High [NAC] in obese individuals -> increased anaphylactoid reactions

PK / PD

Vd - 0.5L/kg
83% protein binding
Study of PK challenging due to metabolism to sulphur compounds (cysteine, GSH, methionine, cystine, disulphides) that are not easily / routinely measured
- Also complications in measuring free vs bound NAC
PO NAC
- PO bioavailability 10-30% (due to first pass metabolism)
- Possibly effective in hepatic tissue in first pass
- Conflicting data if affected by activated charcoal
- Peak concentration ~1.4 hours
- Elimination t1/2 2.5hr
- Significant inter-subject variation regarding peak concentration
IV NAC
- Half-life 2.27hr after 600mg IV NAC (based on free NAC)
- Steady state conc. 35mg/L after standard IV protocol
- Reduced clearance in ESRF and severe liver failure
Limited controlled head-to-head trials but probably no difference on efficacy based on route
- PO NAC associated with more N+V (20% vs 7%)
- IV NAC associated with anaphylactoid reactions (14-18%, although lower (2-6%) in later reports)
  - Related to non-IgE-mediated histamine release
  - Appears to be rate and concentration dependent
  - APAP inhibits mast cell degranulation - higher concentrations protective

Role in Toxicity

APAP (paracetamol)
Also been investigated as treatment for a number of xenobiotics where reactive or free radicals are associated. Best evidence available for
- Amatoxins (Amanita phalloides / death cap)
  - Similar mechanism of delayed hepatotoxicity (centrilobular hepatic necrosis and GSH depletion)
  - Retrospective studies demonstrating lower mortality with NAC vs. Supportive care alone
  - Reduction in hepatotoxicity not shown in animal studies however
Carbon tetrachloride
Other agents - however not studied well for definitive recommendation as treatment generally:
- Acrylonitrile
- Cadmium
- Chloroform
- Cyclophosphamide
- 1,2-dichloropropane
- Doxorubicin
- Eugenol (Clove oil) and pulegone (Pennyroyal oil)
  - Reasonable based on similar mechanism of toxicity to APAP
- Ricin
- Zidovudine
- Cisplatin
  - In vitro studies with reduced nephrotoxicity
Chronic Sodium valproate use
- No evidence for acute toxicity
- 2,4-diene valproic acid (metabolite) may undergo reduction reaction with hepatic GSH
Reduces hepatic graft failure during organ procurement

Adverse effects

Oral NAC

GIT symptoms – nausea, vomiting, flatus, diarrhoea, GORD
Urticaria is rare
Effervescent form presented as sodium salt
- 7g sodium load for 60kg dose
- Consider risk in children and those on sodium restrictions
Increase in ALT noted in one study where PO NAC co-administered with ondansetron
- Mechanism unknown

IV NAC

14-18% (although not really reflected in reality) of rate/concentration-related anaphylactoid reactions
- More common with lower [APAP] - 25% if [APAP] <150mg/L, 3% if >300mg/L
- APAP suppresses histamine release
- Actions:
  - NAC should be continued with mild/moderate reactions, with close observation and treatment if required. Skin reactions are usually transient.
  - NAC should be temporarily stopped in severe reactions
  - The mainstay of treatment is antihistamines
  - Once reaction resolves, restart NAC after 1 hour at a lower rate (if still indicated)
    - Worse outcomes in withholding NAC where it was indicated rather than continuing and managing the side effects
  - Consider switch to PO NAC if available
Mild (6%) / moderate (10%) reactions – cutaneous reactions, nausea, vomiting
Rare (1%) - bronchospasm, hypotension, angioedema
Suppresses clotting factors and increases INR in healthy volunteers
- Seen within an hour of the infusion
- Peaks at 16 hours and rapidly normalises after infusion
- Typically INR < 1.5-2.0
- This effect should be considered when using the King's College criteria

Dosing

Multiple protocols exists – see local guidelines
- Can be given PO or IV but there appears to be a slight clinical benefit with IV administration
- Theoretical benefit of hepatic uptake of NAC due to high first-pass metabolism
Regimens designed to decrease peak [NAC] whilst rapidly getting to steady state, and reducing adverse effects, in an attempt to match [NAC] with [NAPQI]
Thresholds to stop treatment are unclear
- Current thinking is if [APAP] is undetectable and [AST] or [ALT] is normal NAC should be should
- Otherwise NAC should be continued until [APAP] not detectable and [AST]/[ALT] has significantly decreased with no evidence of hepatic failure
  - No validated criteria for what significant means. Suggestions have included:
    - Decreasing serial [AST]
    - [AST] < 1000IU/L
    - [AST]/[ALT] ratio of 0.4
NAC dosing protocols based on ingestion of 16g of APAP
- - Cases of hepatotoxicity despite IV NAC have occurred in the setting of ingestions >16g
    - No reported failures in PO NAC, but probably attributed to higher total dose of NAC
Considerations to increase NAC dose include:
- Massive overdose
- Prolonged / significantly elevated [APAP]
- While patient is on IHD/CRRT
  - Extraction ratio 50-76% in IHD, clearance with CVVHDF is 42mL/kg/h (extraction ratio 13%)
  - Should double NAC infusion rate in IHD, but not in CVVHDF
- - In obesity, consider capping weight at 100kg
    - Due to increased anaphylactoid reactions due to higher concentration
    - However, this has not been studied

IV NAC

US protocol - 150mg/kg given in 1st hour, then 50mg/kg given over 4 hours, followed by 100mg/kg over 16 hours
SNAP – 100mg/kg over 2 hours, 200mg/kg over 10 hours
- Reduction of anaphylactoid reactions (31% to 5%) in an RCT but underpowered for efficacy
Australia – 200mg/kg over 4 hours then 100mg/kg over 16 hours
- No difference in hepatotoxicity
- Reduced anaphylaxis rate
Multiple weight-based calculations may contribute to medication error (one retrospective study suggested an error rate of 33%!)

PO NAC

140mg/kg loading dose
Then 4 hours after, 70mg/kg q4h for 17 doses
Total dose 1330mg/kg
Effervescent PO formulation 2.5g and 500mg tablet

References

Nelson LS, Goldfrank LR. Goldfrank’s toxicologic emergencies. 11th ed. New York Mcgraw-Hill Education; 2019.