N-acetylcysteine, glutathione and NAPQI in paracetamol overdose
N-acetylcysteine (NAC) is the specific antidote (a medicine that acts directly against one poison) for paracetamol overdose: it refills glutathione, a protective liver molecule that neutralises the harmful chemical NAPQI.
Remember
N-acetylcysteine refills the liver's glutathione so that NAPQI is neutralised; it does not remove paracetamol itself, and it is most effective when started within about 8 hours but is still given later when liver injury is likely or has developed.
Memory aid
glutathione is the liver's sponge for NAPQI, an overdose uses the sponge up, and NAC lets the liver make more
Picture glutathione as a sponge that soaks up NAPQI: an overdose uses the sponge up, and NAC lets the liver make more.
Most of each paracetamol dose is made harmless and excreted. A small share of the dose is changed into NAPQI (N-acetyl-p-benzoquinone imine) by cytochrome P450 enzymes, which are liver enzymes that break down drugs. NAPQI is a reactive chemical that damages cell proteins.
Glutathione is a protective molecule made by liver cells, and it neutralises NAPQI as quickly as it appears. In a large overdose, glutathione runs out, NAPQI builds up, and liver cells die (this is called hepatocellular necrosis).
N-acetylcysteine (NAC) is a glutathione precursor, which means the liver can use it as a building block for making glutathione. It refills the stores, and NAPQI can be neutralised before it injures liver cells. NAC does not remove the paracetamol itself; it helps the liver cope with NAPQI.
NAC works best when started within about 8 hours of the overdose. Later treatment is still given when the dose taken or the blood paracetamol level makes liver injury likely, and also when liver injury has already developed. Damage that has already happened is not reversed by NAC, which is why starting early matters.
Paracetamol overdose is often silent in the first 24 hours, so the blood paracetamol level and the dose taken, not symptoms, guide treatment. In the UK, after a single acute overdose at a known time, a paracetamol level taken at least 4 hours afterwards is marked on a treatment line, which charts risk against time and shows who needs NAC.
Key facts
- Antidote
- N-acetylcysteine (NAC) is the specific antidote for paracetamol overdose.
- Made by
- Cytochrome P450 enzymes in the liver make NAPQI from paracetamol.
- What runs out
- A large overdose uses up the liver's glutathione, so NAPQI builds up.
- Best timing
- NAC works best when started within about 8 hours of the overdose, and it is still given after that when liver injury is likely or has already developed.
- Limit
- NAC helps prevent liver injury, but damage that has already occurred is not reversed by it.
- Silent start
- Symptoms are often absent in the first day, so the blood paracetamol level and the dose taken guide treatment.
Exam traps
- Activated charcoal (a fine black powder that binds drug that is still in the gut) is decontamination, which reduces how much drug is absorbed, and not an antidote: it works best within 1 hour of the drug being taken and does nothing to paracetamol that has already been absorbed and converted to its harmful by-product.
- N-acetylcysteine does not work mainly by blocking the cytochrome P450 enzymes that make NAPQI: its main action is to refill glutathione so that NAPQI is neutralised after it has formed.
- Liver injury from a large paracetamol overdose is predictable and dose related, unlike immune-mediated injury (an immune attack on the liver), which is unpredictable and unrelated to dose.
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