Paracetamol poisoning
Acetaminophen (paracetamol, acetyl-p-aminophenol) is an over-
the-counter analgesic antipyretic drug that lacks anti-inflammatory
activity.
Its action is mainly due to the central nervous system inhibition of
prostaglandin E2 via direct inhibition of cyclooxygenase (Cox-2).
1. Absorption: ranges from 30 minutes to 2 hours according to oral
preparation and is almost entirely absorbed by 4 h.
2. Oral bioavailability: 60-98%.
3. Volume of distribution: 0.9L/Kg, with low protein binding
capacity.
• Paracetamol is extensively metabolized in the liver via phase II reactions.
• Most of the administered dose (90%) is excreted as glucuronide and
sulfate conjugates and only very little amount (<5%) is excreted
unchanged in the urine.
Phase II • A small amount is excreted as cysteine conjugate.
• A small portion is metabolized via phase I reactions (oxidation by cytochrome P450
(CYP2E1&CYP2A6) liver microsomal enzymes) to yield the highly electrophilic
toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI).
• This metabolite is normally detoxified by interaction with the cellular nucleophile
glutathione (γ-glutamyl-cysteinyl-glycine, or GSH) in a reaction mediated by the
enzyme glutathione-S-transferase.
Phase I • The formed conjugate loses glutamate and glycine and so paracetamol-cysteine
conjugate is formed, the latter is then excreted as mercapturic acid in the urine.
In therapeutic doses, it is a safe drug, considered even safer than NSAIDs.
The therapeutic dose is 10-15mg/Kg/dose (4000mg/ day).
On the other hand, it is extremely toxic to the liver as well as other organs in high doses.
Toxic effects are usually expected in adults with recent ingestion of more than 7500 mg (15 adult tablets).
At high doses of paracetamol, conjugation pathways (glucuronidation and sulfation) become
saturated and greater amounts of paracetamol are metabolized via the toxic pathway (phase I).
Therefore, glutathione stores become depleted, and glutathione re-synthesis is diminished and
becomes unable to compensate the GSH loss due to cysteine loss.
The formed unconjugated metabolite (NAPQI) becomes then bound to cellular macromolecules
(proteins, enzymes, DNA, lipids, ..etc) causing cellular necrosis.
1. Presence of liver disease.
2. Liver microsomal enzyme inducers like
barbiturates, alcohol, phenytoin, ..etc (due to
increased formation of the toxic metabolite).
3. Fasting and poor nutrition (due to
glutathione depletion).
4. Vitamin A overdoses (due to depletion of
glucuronic acid).
5. Pregnant woman.
The clinical course of acute acetaminophen toxicity can be divided into four stages:
• Up to 24 hrs after ingestion
Stage 1 and characterized by
(Nonspecific) anorexia, nausea, vomiting
: &diaphoresis.
• 24-72 hrs after ingestion.
Stage 2 (
clinical • Signs and symptoms
hepatotoxici apparently improve but there
ty): is pain in the right upper
quadrant of the abdomen.
• 72-96 hrs after ingestion.
• Transaminases (aspartate aminotransferase and alanine
Stage 3 (Maximal aminotransferase) become extensively elevated by about
100 folds.
hepatotoxicity):
• It is the recovery stage of drug overdose which occurs 7-8 days
after ingestion.
• Signs &symptoms resolve and results of laboratory tests return
Stage 4 to normal if stage 3 is survived.
(Recovery or • In some cases,the stage is marked by complications of massive
liver necrosis leading to fulminant liver failure with
death): complications of coagulation defects, low blood sugar, kidney
failure, brain swelling, sepsis, multiple organ failure, and death
1. History:
Dose.
Time of ingestion is very important.
Co-ingestion.
High-risk patients.
2. APAP level (Rumack-Matthew nomogram):
Estimates the risk of toxicity based on the serum
concentration of paracetamol at a given number of hours
(4hrs) after ingestion.
Because of paracetamol may still be in the process of
being absorbed from the gastrointestinal tract Therefore,
a serum level taken before 4 hours is not recommended.
The nomogram is divided into three levels of risk, namely possible, probable and high.
• Patients with serum concentration greater
High than 300 mg/dL at 4 hours after
risk ingestion are considered at high risk.
• (give antidote).
• Patients with serum concentration
Probab of 200 mg/dL at 4 hours after
le ingestion are considered at
probable risk.
risk • ( Give antidote).
Possib • Patients with serum concentrations
greater than 150 mg/dL at 4
le hours after ingestion are
considered at possible risk.
risk • ( No need for NAC).
Gastric
decontaminat
N-
acetylcystei
Othe
ion ne rs
Especially in cases of very early presentation or
co-ingestion of agents that delay GI absorption.
Gastri
Hepatotoxicity of paracetamol is uncommon in
c
patients treated within 10 hours after ingestion.
lavage
Paracetamol absorption from the
gastrointestinal tract is complete within two
hours under normal circumstances, so
Activa
decontamination is most helpful if performed
ted
within this timeframe. charco
al
Gastric lavage may be considered if the
amount ingested is potentially life-threatening
and the procedure can be performed within 60
minutes of ingestion.
Activated charcoal is the most common gastrointestinal
decontamination procedure.?
1. It adsorbs paracetamol, reducing its gastrointestinal absorption.
2. Administering activated charcoal also poses less risk of aspiration
than gastric lavage.
It appears that the most benefit from activated charcoal is gained if
it is given within 30 minutes to two hours of ingestion.
There was reluctance to give activated charcoal in paracetamol
overdose, because of the concern that it may also absorb the
oral antidote acetylcysteine but Intravenous acetylcysteine has
no interaction with activated charcoal.
The ideal antidote of paracetamol toxicity is N-
acetylcysteine.
Mechanism of antidote:
1. It works mainly by acting as a glutathione precursor,
supplying the amino acid cysteine (the rate-limiting step
for GSH biosynthesis).
2. It may act also by direct conjugation with the toxic
metabolite.
3. Moreover, its antioxidant effect may suppress the lipid
peroxidation reaction initiated by NAPQI.
Dose:
1. N-acetylcysteine is administered orally at a loading dose
of 140 mg/kg,
2. followed by 17 doses, each of 70 mg/kg every 4 hours
(total dosing time is 72 hours).
3. It is most effective when given within 8 hours of
ingesting acetaminophen.
It should be mentioned that activated charcoal should
not be given with N-acetylcysteind as it may decrease
the efficacy of the latter by adsorbing it.
1. Liver microsomal enzyme inhibition:
Liver microsomal enzyme inhibition may also decrease
paracetamol hepatotoxicity through suppressing the
formation of the toxic metabolite by suppressing
cytochrome P450 liver microsomal enzymes.
2. Calcitriol:
Calcitriol, the active metabolite of vitamin D3, appears to be a
catalyst for glutathione production.
Calcitriol was found to increase glutathione levels so It has been
proposed that co-administration of calcitriol, via injection, may
improve treatment outcomes.
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