Date post: | 05-Dec-2014 |
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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