Why it is dangerous

Acetaminophen is normally conjugated and excreted. In overdose those pathways saturate and more is shunted to NAPQI, a toxic metabolite detoxified by glutathione. When glutathione is exhausted, NAPQI causes centrilobular hepatic necrosis.

N-acetylcysteine works by replenishing glutathione — which is why it must be given before the damage, not after it appears.

The clinical course, in four phases

0–24 h — asymptomatic, or nausea and vomiting. Liver tests are normal. This is the trap: a well patient at 4 hours tells you nothing
24–72 h — right upper quadrant pain, transaminases rising
72–96 h — peak hepatotoxicity: jaundice, encephalopathy, coagulopathy, acute kidney injury, lactic acidosis. This is when people die
4 days–2 weeks — recovery, or liver failure

Assessment

Serum acetaminophen level at 4 hours post-ingestion, or immediately if later than 4 hours. A level before 4 hours is uninterpretable
Plot on the Rumack–Matthew nomogram — valid only for a single acute ingestion at a known time
Also send: transaminases, INR, creatinine, bicarbonate, glucose, blood gas, and salicylate level (co-ingestion is common)
Activated charcoal if presenting within 1–2 hours and the airway is protected

When to treat

Give N-acetylcysteine if any of:

The level is above the treatment line on the nomogram
Time of ingestion is unknown, the ingestion was staggered, or presentation is delayed beyond 8 hours — treat first, ask questions after
There is any evidence of hepatotoxicity
The history suggests a toxic dose (> 150 mg/kg, or > 10 g) and the level will not be back promptly

NAC is close to 100% effective within 8 hours of ingestion, and its benefit falls steadily thereafter — but it still helps in established liver failure, so late presentation is never a reason to withhold it.

The commonest adverse effect is an anaphylactoid reaction — flushing, rash, bronchospasm. It is rate-related, not true allergy: slow or pause the infusion, give an antihistamine, and restart. Do not abandon treatment.

Higher risk at lower doses

Chronic alcohol use, malnutrition, anorexia, prolonged fasting, and enzyme-inducing drugs (carbamazepine, phenytoin, rifampicin, isoniazid) all deplete glutathione or increase NAPQI.

When to call the transplant centre

King's College criteria for acetaminophen-induced liver failure:

Arterial pH < 7.3 after adequate fluid resuscitation, or
All three of: INR > 6.5, creatinine > 300 µmol/L, and grade III–IV encephalopathy

A rising lactate and a rising INR after day 2 are the practical bedside warnings.

Before discharge

Every intentional overdose needs a psychiatric and suicide risk assessment, and a conversation about access to means. That is part of the medical management, not an afterthought.