PARACETAMOL POISONING

1. PARACETAMOL
POISONING
DR SAURABH PATHAK
JR-1, FORENSIC MEDICINE

2. What will be covered ?
1. Introduction to Paracetamol.
2. Metabolism of Paracetamol.
3. Mechanism of Toxicity.
4. Clinical features.
5. Work up & diagnosis.
6. Management.
7. Postmortem findings.
8. Medicolegal importance.

3. What is Paracetamol ?

An NSAID.

Phenacetin (de-ethylation)→ Paracetamol
(Active metabolite)
Phenacetin- An analgesic & anti-pyretic but
Carcinogenic at therapeutic doses.
Also Causes Nephropathy

Paracetamol ~ Acetaminophen.

“Paracetamol"- used in India.

“Acetaminophen"- used in US, Canada, and some
other countries.

4. Chemical Name- N- acetyl- para- aminophenol
(APAP) / Para-acetylaminophenol.
Para-acetylaminophenol- Paracetamol
Para-acetylaminophenol- Acetaminophen
How do we metabolize Paracetamol ?

Well absorbed orally.

Oral Bio-availability- 70-90%

Rectal Bio-availabilty- 30-70%

Metabolized in liver.

Excretion in Urine.

Half life (t1/2)- 2-3 hrs.

5. Metabolism via 4 pathways-
1. Glucuronidation (60%).
2. Sulfonation (35%).
3. Conjugation with Cysteine (3%).
4. Cytochrome P450 mediated N-hydroxylation to
form N-acetyl-p-benzoquinoneimine (NAPQI)
(1%).
Side effects- Nausea, rashes, leukopenia (rare).

7. Paracetamol Poisoning
Mechanism of Toxicity-

NAPQI is an strong oxidizing agent.

NAPQI is normally detoxified by conjugation with reduced
Glutathione and excreted in Urine as Mercapturic acid and
Cysteine conjugates.

If glutathione stores run-out, the toxin (NAPQI) forms
covalent bonds with cell proteins (of liver and kidney cells),
denaturing them and leading to cell death (Liver and kidney
necrosis).

8. Paracetamol poisoning may be Acute or Chronic.
Acute Poisoning-

Mostly suicidal, rarely accidental.

Homicidal poisoning is virtually unknown because of large
dose required.
Doses- 1 tablet- 500 mg.
20 tablets = 10 gms- may produce severe
Hepatotoxicity.
40-50 tablets = 20-25 gms- Fatal.
Children- 150 mg/kg body wt.

More dangerous in alcoholics, so they develop toxicity in
lower doses.
Fatal Period- 2-4 days.

9. Signs and Symptoms-
Clinical Course can be divided into 3 phases.
Phase I- 30 min- 24 hrs.
- Nausea, Vomiting, Diaphoresis, Pallor, mild
Drowsiness.
Phase II- 24-48 hrs.
- Patient is symptoms free.
- LFT abnormal.
Phase III- 3-5 days.
- S/S of severe hepatic necrosis (asterixis, jaundice,
Right Upper Quadrant tenderness, hemorrhages,
Coagulation defects, fetor hepaticus, hypoglycemia)
- Renal failure. (Rare)
- Cardiomyopathy. (Rare)

10. Chronic Poisoning-
Scenario- Person consumes large doses over years for
pain control.

More common in Alcoholics, AIDS patients
(depletion of glutathione).

Patients receiving Cyt P450 inducers (Barbiturates,
Carbamazepine, Isoniazid, Phenytoin, Rifampicin)

In Children where doses have been wrongly
calculated.
Clinical features- Hypothermia, Anorexia, Vomiting
Hepatomegaly, Lethargy, Oliguria.

11. Work up & Diagnosis

Gastric lavage, Blood, Urine for Toxicological analysis.

Routine blood tests- CBC, LFT, RFT, electrolytes, PT-INR.

Marked elevation of Liver enzymes, (>1000 IU/L) is
typically seen.

Deranged PT is seen.

PCM levels are assessed in blood by enzyme
immunoassay and High performance liquid
chromatography (HPLC).

12. 
Serial LFT and RFT monitoring (to know exact status
of Acute liver injury and Acute kidney Injury).

Coagulation Profile monitoring and Correction with
Vitamin K, FFP etc.

Check for systemic bleed- Hematemesis, Malena,
Hematuria etc.

Check for hepatic encephalopathy if patient in altered
sensorium.

13. Rumack Matthew Nomogram

14. How do we manage ?

Induce Vomiting or Gastric lavage.

Activated Charcoal- It should not be given if NAC or
methionine are intended to be administered.

3 Antidotes- N- acetyl Cysteine,
- Methionine,
- Cysteamine.

N Acetyl cysteine (NAC) - Oral- Loading dose- 140 mg/kg
followed by 70 mg/kg every 4 hrs for 17 doses.

NAC has foul smell and taste. Thus if given orally, it must
be diluted with soft drinks to make 5 % solution. The
solution must be consumed within 1 hr of preparation.

15. Intravenous -150 mg/kg over 15 min, followed by same dose iv
over next 20 hrs.
Golden time for administration- within 8 hrs of
ingestion.
Practically ineffective if started 16 hrs or later after ingestion.
MOA of NAC-
1. Prevents binding of NAPQI to hepatocytes.
2. Directly binds to NAPQI.
3. Enhances synthesis of additional Glutathione.
4. Acts intracellularly as a Glutathione substitute.
5. Reduces NAPQI back to Paracetamol.

16. Side effects of NAC- Anaphylactoid reactions.
- Related to dose-related histamine release.
Common features are itching and urticaria, and in severe
cases, bronchospasm and hypotension.
Rx-Temporary discontinuation of NAC + antihistaminics.
Methionine- Oral antidote
- Glutathione precursor.
- Dose- 2.5 gm at 4 hrly interval upto 4
doses.
Cysteamine- Obsolete because of less efficacy.

17. Poor Prognostic Factors
Liver transplantation- When fulminant liver failure
develops, Liver transplantation
is the definitive and only treatment.
• Metabolic Acidosis (pH < 7.3) at or beyond 24
hours following the overdose.
Or

Serum creatinine > 3.38 mg/dL) plus PT >100 secs
plus encephalopathy grade 3 or 4.

18. Post mortem findings
Apart from toxicological analysis
of viscera, mainly 3 organs are to
be examined.
Liver, Kidney and Heart.
Liver- Acute centrilobular Hepatic Necrosis.
Kidney- Acute tubular necrosis.
Heart- Myocardial necrosis.
In Brain- Cerebral edema may be found.

19. Medico-legal Importance

Paracetamol toxicity is mostly suicidal.

Rarely, it can be Accidental.

Homicidal Poisoning of PCM is not known as
large doses are required.

A survivor of PCM poisoning can donate Liver
for transplantation after complete recovery.

20. References
1. Textbook of Forensic medicine and toxicology by
Anil Agrawal.
2. Review of Forensic Medicine and Toxicology by
Gautam Biswas.
3. Essentials of Medical Pharmacology by K. D.
Tripathi.
4. Davidson's Principles and Practice of Medicine.