Introduction
Paracetamol (acetaminophen) is a widely used anti-pyrexic and analgesic, with similar efficacy in these areas to aspirin, however, unlike aspirin and NSAIDs it has virtually no anti-inflammatory properties.
It is the first analgesic recommended on the WHO Pain Ladder. It is often used in combination with opiates, and can reduce the opiate requirement.
At doses of <4g/day (usually in 1g four times per day) it is considered very safe, even in those with existing liver disease.
At doses higher than this, it can cause hepatotoxicity, which is dose and age dependent. Older patients metabolize paracetamol more slowly.
Metabolism
- Undergoes metabolism in the liver via two main pathways
- Glucuronide pathway – accounts for about 60% of metabolism (non-toxic metabolites)
- Sulphate pathway – accounts for about 30% (non-toxic metabolites)
- Cytochrome P-450 (CYP-450) pathway – accounts for 5-10% of metabolism. Creates a toxic metabolite – NAPQI
- Glutathione binds to NAPQI in the bloodstream and prevents its toxic effects
- In paracetamol overdose, glutathione is depleted and NAPQI binds to cellular proteins, preventing their function and causing cell death. Acetylcysteine (NAC) – the antidote used in poisoning – is a glutathione donor
- <5% excreted unchanged by kidneys
In overdose
Management of overdose is covered in Paracetamol Overdose
- The Glucuronide pathway quickly becomes saturated, and much of the excess is instead metabolized by the CYP-450 pathway, creating an excess of NAPQI
- The excess NAPQI depletes the stores of glutathione
- Once 70% of stores have been depleted, toxic effects of paracetamol are seen
- An estimate of a toxic dose is roughly 150mg/Kg
Risks of overdose
- Relatively low
- Untreated, less than 10% of patients have liver damage
- Untreated mortality rate <2%
- Treated (with N-acetylcysteine) mortality rate <0.4%
In Liver Disease
- Pracetamol is safe to use in patients with chronic liver disease
- The metabolism is often slower than in patients without liver disease, but, it does not affect the percentage of paracetamol metabolized by the cytochrome P-450 pathway, not levels of glutathione
- There are some studies that suggest it is toxic in alcoholic liver disease, although clinical evidence does not support this1