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Paracetamol (Acetaminophen) poisoning

Important cause of acute liver failure.

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Liver- highly exposed to drugs and toxins absorbed from the GIT

Phase 1 drug metabolism - alters the parent molecule

Phase 2 - conjugate of the drug or its metabolite with a more water-soluble moiety

Phase 3 - energy-dependent excretion

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Phase 1 pathways

Oxidation, reduction, and hydrolytic reactions

Products of phase metabolism can be readily conjugated or excreted without further modification

Catalyzed by microsomal cytochrome P450 or CYP

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Hepatic expression of CYP enzyme is genetically determined.

Great differences in drug metabolism

In many severe liver diseases - decreased levels of total CYP and reduced hepatic perfusion

Decrease in the clearance of drugs that are rapidly metabolized by the liver

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Phase 2 metabolism (detoxification)

Conjugate of the drug or its metabolite with › glucuronic acid› inorganic sulfate

Highly water-soluble and excreted in bile or urine

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Phase 3 metabolism

Involves the ATP-binding cassette (ABC) transport proteins› cystic fibrosis transmembrane

conductance regulator (CFTR)› canalicular and intestinal copper

transporters› multidrug resistance-related

proteins (MRP)

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Oxidative stress Hepatocytes - activate oxygen (toxic)

Liver has antioxidant mechanisms

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Glutathione

Most important antioxidant in the liver

Liver is the only site of glutathione synthesis

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Cysteine Increases synthesis of

glutathione NADPH - essential cofactor that

requires ATP Relation between energy-

generating capacity of the liver and its ability to withstand oxidative stress

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Highest concentrations of glutathione - in the cytosol

Mitochondria – ROS constantly formed as a by-product of oxidative respiration

Mitochondrial glutathione is maintained by active uptake from the cytosol

Chronic ethanol exposure alters this transport system - predispose to drug toxicity

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Dose related toxicity

Paracetamols Oral contraceptive pills

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INH

Not dose related

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Toxic dose of paracetamol

Single ingestion > 7 to 10 g (150 mg/kg body weight in children)

Fatal cases usually involve doses of at least 15 to 25 g

In heavy drinkers, daily doses of 2 to 6 g have been associated with fatal hepatotoxicity

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Plasma half-life of paracetamol

2 to 4 hours

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Main metabolism

Phase 2 reaction ›Conjugation with sulfate and glucuronide to form nontoxic metabolites in

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Minor route

Phase 1 reaction› Oxidized by hepatic cytochrome P450 enzymes

› Form n-acetyl-p-benzoquinoneimine (NAPQI)

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NAPQI

Toxic Detoxified by conjugation

with glutathione Mercapturic acid

› harmless and water-soluble› renal excretion

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Low glutathione levels

NAPQI produce liver injury Hepatic necrosis occurs

only when concentrations of reduced glutathione fall below a critical level

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Cysteine Stimulates hepatic synthesis of reduced glutathione

Protects the liver

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> 140 mg/kg body weight of paracetamol

Sulfate and glucuronide pathways saturated

Increased amount of paracetamol gets metabolized to NAPQI

Glutathione levels depleted Free NAPQI - centrilobular

necrosis

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Alcohol Induces cytochrome P450

Chronic alcoholics - toxic dose of paracetamol may be as low as two grams

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Malnutrition

Decreases glutathione reserves

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Early manifestations occurring within 12 h

Nonspecific› Nausea and vomiting› Diarrhea› Abdominal pain› Shock

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No features of liver injury in the first 2 days

After 48 to 72 hours› ALT - often between 2000 and 10,000 U/L

› Right upper quadrant tenderness

› Jaundice

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6 days Maximal hepatic failure may not be evident until 6 days after ingestion

Hepatic failure Renal failure

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Most important factor affecting mortality

Time of presentation – cysteine within 12 hours abolishes significant liver injury

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Other prognostic factors

Age – Children relatively resistant

Alcohol and fasting › Enhance activity of CYP› Deplete hepatic glutathione

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INDICATORS OF A POOR OUTCOME

Grade IV hepatic coma Acidosis - pH less than 7.30 PT - Twofold prolongation Renal failure - Serum creatinine

> 3.3 Falling ALT with worsening PT

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Rumack-Matthew nomogram

Risk of liver injury

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When should serum paracetamol level be obtained for Rumack-Matthew nomogram?

Between 4 and 24 h after ingestion - reliable indicator

Determine acetaminophen blood levels at the time of presentation

Blood levels within 4 hours of ingestion may not be a reliable estimate - delayed gastric emptying

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N-acetylcysteine

Antidote of choice Slow bolus IV injection followed by infusion

Oral

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Give immediately before the serum level is known

Most effective if started within 8 to 10 h of an overdose

Discontinue - If the level is subsequently shown to be nontoxic

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Level > 300 ug/mL 4 h after ingestion

Predictive of severe damage

< 150 ug/mL - hepatic injury highly unlikely

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Side effects of NAC

Nausea, vomiting, and epigastric discomfort

Rash Angioedema Fatal shock Close supervision and only for

appropriate indications

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Methionine In patients known to be sensitized to NAC, methionine is probably just as effective

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Wide-bore gastric tube

< 4 hours - empty the stomach

Activated charcoal if < 4 h of › does not interfere significantly with acetylcysteine therapy

Osmotic cathartics –not indicated

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Etiology-specific therapy

Paracetamol poisoning - NAC Amanita - Penicillin G and NAC HSV – Acyclovir AIH - Methylprednisolone HBV - Lamivudine AFLP/HELLP - Delivery of fetus

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Amanita mushroom poisoning

Reduce the toxin load› Gastric lavage› Instillation of charcoal

Hemodialysis - remove toxins from the serum

Lower entero-hepatic toxin load - Uncertain › pencillin, cytochrome c, and silymarin

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Liver transplantation

Life-saving