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Paracetamol poisoning

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PARACETAMOL
POISONING
DR SAURABH PATHAK
JR-1, FORENSIC MEDICINE

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What will be covered ?
1. Introduction to Paracetamol.
2. Metabolism of Paracetamol.
3. Mechanism of Toxicity.
4. Clinical...

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What is Paracetamol ?

An NSAID.

Phenacetin (de-ethylation)→ Paracetamol
(Active metabolite)
Phenacetin- An analgesic &...

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Paracetamol poisoning

  1. 1. PARACETAMOL POISONING DR SAURABH PATHAK JR-1, FORENSIC MEDICINE
  2. 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. 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. 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. 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).
  6. 6. 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).
  7. 7. 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.
  8. 8. 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)
  9. 9. 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.
  10. 10. 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).
  11. 11.  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.
  12. 12. Rumack Matthew Nomogram
  13. 13. 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.
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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.
  18. 18. 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.
  19. 19. 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.

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