NAC
N‑acetylcysteine (NAC)
Generic Name
N‑acetylcysteine (NAC)
Mechanism
N‑acetylcysteine (NAC) is a *semisynthetic derivative of the amino‑acid cysteine* that functions through several complementary pharmacologic pathways, which collectively confer its therapeutic utility.
1. Glutathione precursor – NAC is deacetylated by hepatic *acetyl‑cysteine hydrolase* to cysteine, the rate‑limiting substrate for the synthesis of the intracellular antioxidant glutathione (GSH). By restoring intracellular GSH levels, NAC promotes detoxification of reactive oxygen species (ROS), protects hepatic mitochondria, and mitigates oxidative damage in acetaminophen (APAP) metabolism.
2. Direct antioxidant – Cysteine residues in NAC can directly scavenge free radicals and reactive glutathione disulfide (GSSG), thereby reducing oxidative stress independent of GSH synthesis.
3. Disulfide bond reduction – The thiol group in NAC facilitates the breakdown of disulfide bonds in extracellular mucus, decreasing its viscosity and viscoelasticity. This property underlies its mucolytic action in airway diseases.
4. Receptor modulation – NAC attenuates glutamate‑mediated excitotoxicity by inhibiting the cystine‑glutamate antiporter x_c⁻, thereby reducing extracellular glutamate synthesis and subsequent neuronal over‑excitation.
5. Pro‑inflammatory cytokine inhibition – By restoring redox balance, NAC blunts nuclear factor κB (NF‑κB) activation, consequently lowering pro‑inflammatory cytokine release (e.g., IL‑1β, TNF‑α).
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Pharmacokinetics
| Parameter | Typical Value | Notes |
| Bioavailability | Oral: ~10–15% | Highly variable; food reduces absorption; delayed-release or enteric formulations improve bioavailability. |
| Absorption | Rapid from gut (~30–60 min) | Peak plasma levels in 30–90 min; biphasic decline. |
| Distribution | Widely distributed; binds ~8% to plasma proteins | 2–3 L/kg in plasma; crosses blood‑brain barrier. |
| Metabolism | Primarily hepatic via conjugation (glucuronidation, sulfation) | No major CYP450 involvement; safe in hepatic impairment if dose adjusted. |
| Half‑life | Intravenous: ~5 h (1 h for initial rise) | Oral: ~1–3 h; long terminal phase due to GSH synthesis. |
| Elimination | Renal excretion of metabolites (cysteine, mercaptolysine) | Renal function does not significantly affect plasma concentrations. |
Key dosage infusion: Intravenous 150 mg/kg over 15 min (initial loading), followed by 50 mg/kg over 4 h, then 100 mg/kg over 16 h for APAP overdose protocols (see Dosing section).
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Indications
- Acetaminophen (APAP) overdose – Gold‑standard antidote; derived from 1978 protocols.
- Chronic obstructive pulmonary disease (COPD) – Adjunct to bronchodilators for severe exacerbations, primarily in patients who have high sputum viscosity or cholinergic mucus hypersecretion.
- Cystic fibrosis (CF) – Reduction of sputum viscosity and improvement in pulmonary function tests; used pre‑ and post‑inhalation therapy.
- Bronchiolitis in infants – Mucolytic benefit in moderate to severe disease.
- Liver disease – Evidence for chronic use in chronic hepatitis C and non‑alcoholic fatty liver disease (NAFLD) to reduce oxidative stress; not first‑line therapy.
- Severe sepsis & septic shock – Adjunctive therapy for GSH depletion and ROS mitigation; adjunctive benefits remain investigational.
- Pesticide, organophosphate & cyanide toxicity – Potential benefit in reducing oxidative stress; limited to supportive use.
- Psychiatric prophylaxis – Off‑label for bipolar disorder & obsessive‑compulsive disorder; evidence is mixed, mainly due to antioxidant mechanism.
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Contraindications
| Category | Details |
| Contraindications |
• Allergy to paracetamol (due to possible cross‑reactivity) • Severe bronchospasm or asthma exacerbation (IV formulation more likely to provoke) |
| Warnings |
• Pregnancy: Category C; use only if potential benefit outweighs risk. • Pediatric: Data limited; dosing individualized. • Chronic Use: May have hair loss, GI disturbances. • Risk of anaphylactoid reactions: IV infusion may cause severe itching, flushing, or bronchospasm. Use slow infusion, premedicate with antihistamines if indicated. • Drug Interactions: Minor interactions with drugs metabolized by CYP450 (none clinically significant); may potentiate the effect of acetaminophen if combined. |
| Precautions | Hepatic impairment: safe; monitor transaminases in chronic use.Renal impairment: minimal impact; no dose alteration needed. |
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Dosing
> Note: All dosing can be adjusted for patient weight in kg.
Monitoring
| Parameter | Frequency | Rationale |
| Serum acetaminophen concentration (for overdose) | After loading dose, then hourly until 20 μg/mL | Guides continuation vs. cessation of therapy |
| Liver Function Tests (ALT, AST, bilirubin) | Baseline, then day 3–5, monthly for chronic use | Detectz early hepatotoxicity |
| Renal function (serum creatinine, BUN) | Baseline, then at 24–48 h for IV, monthly if chronic | Though generally safe in renal impairment |
| Electrolytes, CBC (especially in high doses) | Baseline, then periodic | Monitor for rare cytolytic events |
| Pulmonary assessment (peak expiratory flow, symptoms) | Every 12–24 h during acute COPD/CF exacerbations | Evaluate response to mucolytic therapy |
| Vital signs during IV infusion | Every 15 min for first 30 min, then hourly | Detect bronchospasm, hypotension, arrhythmia |
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Clinical Pearls
- “Rule of 4‑hour”:
Initiate NAC within 4 hours of acetaminophen ingestion for maximum efficacy. If ingestion was >8 h ago and symptom onset is only mildly elevated, consider 2 nd‑stage dosing based on serum level.
• Dose Scaling = Weight × 0.04 g (IV):
A quick bedside rule: *Dose (mg) = 40 mg × patient weight (kg) × hourly rate (for loading)*. Example: 70‑kg adult → 2500 mg IV loading.
• “Water‑bottled” vs “Full‑filled”:
Oral NAC tablets are often implicated in GI upset; liquid formulation or Solu‑Ca (soft capsule) can significantly improve tolerance.
• Avoid “Prolonged” infusion:
If the patient exhibits infusion‑related bronchospasm, stop infusion, administer diphenhydramine and epinephrine if needed, then restart at 1/8th the rate.
• Importance of *Albumin Binding* in COPD:
COPD patients often have reduced serum albumin; NAC’s efficacy as a mucolytic may not be heavily influenced, but low albumin can predispose to higher free cysteine levels and potential GI discomfort.
• Preventing *Re‑exposure*:
In patients who are at risk for repeat acetaminophen exposure (e.g., during cardiac surgery under high-dose APAP analgesia), administer maintenance NAC (2–3 g/day IV/PO) throughout the high‑risk period to maintain glutathione levels.
• NAC in COVID‑19:
Several observational series suggest that early NAC administration may attenuate cytokine storm in severe COVID‑19; but current guidelines consider it experimental.
• Bioavailability Boosters:
Co‑administration with protein‑rich meals can raise oral NAC plasma peaks by ~25 %, but the benefit must be weighed against potential GI distress.
• Caution in Pediatric Use:
The *lack of robust pediatric dosing data* necessitates cautious weight‑based dosing and close monitoring of GI tolerance.
• Drug‑Drug Interaction Insight:
While NAC has minimal CYP interactions, it can interfere with certain chemotherapeutic agents (e.g., doxorubicin) by virtue of ROS scavenging; oncologists sometimes hold NAC during chemotherapy infusion rounds.
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• *Prepared for healthcare professionals and medical students seeking a concise yet thorough reference on NAC. Leverage this card in clinical decision‑making, exam preparation, and patient education.*