Acetaminophen

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Acetaminophen N-acetyl-P-aminophenol (APAP)
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Paracetamol Overdose

• -Most common drug taken in overdose
• -As little as 12g can be fatal (therapeutic dose
  2.6 gm/24 hour)
• -It is a hepatic and renal toxin (Centrolobular
  necrosis)
• -More toxic if liver enzymes are induced or with
  reduced ability to conjugate toxin (alcoholics,
  phenytoin, phenobarbitone)
• -The safety of acetaminophen depends on the
  availability of electron donors such as reduced
  glutathione (GSH) and other thiol-containing
  substances required to detoxify NAPQI.

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Met pathways of APAP

• 1- Hepatic glucuronide conjugation(40-65)
  Hepatic
  sulfat conjugation(20 - 45)
• 90 inactive metabolites excreted in
  the urine.
• 2- Excretion of unchanged APAP in the urine
  (5).
• 3- Oxidation by P450 cytochromes to NAPQI
  (5-15)
• ? GSH combines with NAPQI
• ? nontoxic cysteine/mercaptate
  conjugates
• ? excreted in urine.

• Hepatic glucuronide conjugation(40-65)
  
• Hepatic sulfat conjugation(20 - 45)

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Mechanism of Toxicity

• The ingested APAP undergo oxidative metabolism by
  CYP- 450 to reactive intermediate metabolite
  (N-acetyl P-benzoquinone imineNAPQI) which is
  rapidly bounded to glutathion ,detoxified
  through conjugation pathway ,and excreted. In the
  presence of adequate GSH stores , there is no
  fear from any toxicity. However, overdose of APAP
  saturate the conjugation pathways and NAPQI
  overwhelms the GSH detoxifi-cation mechanism ,
  finally leading to liver necrosis and may be
  death.

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Paracetamol Metabolism
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What happens to APAP metabolism in an OD
situation?

• 1-Saturation of glucuronidation and sulfation
  pathways
• 2-Amount of APAP metabolized by p450 cytochromes
  to NAPQI increases.
• 3-Normally NAPQI is detoxified by reduced GSH
  (glutathione) and thiol containing substances.
• 4-In OD rate and quantity of NAPQI formation
  overwhelms GSH supply and regeneration
• ? elimination of NAPQI prolonged
• ? free NAPQI binds critical intracellular
  proteins with sulfhydryl groups
• ? cellular dysfunction and cell death.

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Factors which adversely affect APAP metabolism

• 1-Upregulation (i.e. induction) of CYP 2E1 enzyme
  activity
• smoking, barbituates, rifampin, carbamazepine,
  phenytoin, ethanol
• 2-Decreased glutathione stores (malnutrition)
• 3-Frequent dosing interval of APAP.
• 4-Prolonged duration of excessive dosing.

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GSH stores

• Glutathione stores are determined by
• -Age
• -Diet
• -Liver disease
• -Fasting prior ingestion
• -Chronic malnutrition
• -Anorexia
• -Gastroenteritis
• -Chronic alcoholism
• -HIV

• Glutathione replacement by sulfhydryl compounds
• -Eating
• -NAC

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Renal toxicity

• Organ dysfunction results everywhere where local
  oxidative metabolism (via p450) creates NAPQI
  that cannot be detoxified ? direct toxicity
• cytochrome P-450 enzymes produce NAPQI in the
  renal tubules ? NAPQI binds cellular
  macromolecules ? acute tubular necrosis.
• (25 of hepatotoxic cases) Hepatorenal
  Syndrome Volume depletion

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Other organs damaged

• Heart ? myocarditis
• Pancreas ? pancreatitis
• It is controversial whether these entities are
  part of multisystem organ failure (MSOF) from
  fulminant hepatic failure (FHF) or from the local
  accumulation of toxic metabolites.

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Clinical presentation

• Phase 1 (few hrs after ingestion up to 24 hr)
  Malaise , nausea , vomiting and diaphoresis.
• Phase 2 (24-72 hrs after ingestion) Increase in
  liver enzymes, serum bilirubin , prothrombin time
  , and pain in the right upper abdominal quadrant.
• Phase 3 (72-96 hrs after ingestion) Peak in the
  liver function, altered consciousness,
  hypoglycemia, jaundice , and coagulation
  abnormalities. Hepatic failure can develops in
  4th or in the 5th day if hepatic damage is sever.
• Myocardial necrosis, pancreatitis , heamolytic
  anemia and skin rashes may develop but are rare.
• Phase 4 (7-10 days after ingestion) Liver
  enzymes abnormalities reaching resolution. If
  hepatic damage is massively sever sepsis and
  death may occure at 7-10 days

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Laboratory analysis

• 1-Determination of plasma APAP level.
• 2-Monitoring liver profile including serum ALT,
  AST , bilirubin , glucose , prothrombin time,
  platelet countetc
• 3- Determination of kideny functions by measuring
  plasma creatinine and BUN.
• 4-ECG for assessment of myocardial injury.
• 5- Urine analysis.

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Management Steps

• General measures
• (if the patient is presented to ER within 4 hrs
  of ingestion
• -Gastric lavage
• -Activated charcoal ,cathartics (saline sulfate
  are prefered to enhance sulfate metabolic
  pathway).
• glucose, bicarbonate, Vit K for elevated
  prothrombin time
• lt8 hours
• -Take level of APAP after four hours (Peak
  concentration at 4 hrs then hepatic metabolism)
• -Start N-aceylcysteine (antidote) if APAP
  concentration is high APAP is on or above
  nomogram tx line.
• -Patients should be advised to return to hospital
  if vomiting or abdominal pain develop or reoccur.

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Nomogram
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Management 2

• gt8 hours
• Urgent action required because the efficacy of
  NAC declines progressively from 8 hours after the
  overdose
• Therefore, if gt 150mg/kg or gt 12g (whichever is
  the smaller) has been ingested, start NAC
  immediately, without waiting for the result of
  the plasma paracetamol concentration
• gt24 hours
• Still benefit from starting NAC

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N-acetylcysteine (Antidote)

• Supplies glutathione precursor (cysteine)
• Dosage for NAC infusion
• (1) 150mg/kg IV infusion in 200ml 5 dextrose
  over 15 minutes, then
• (2) 50mg/kg IV infusion in 500ml 5 dextrose over
  4 hours, then
• (3) 100mg/kg IV infusion in 1000ml 5 dextrose
  over 16 hours
• Side-effects
• Flushing, hypotension, wheezing, anaphylactoid
  reaction
• -Alternative is methionine PO , it increase GSH
  synthesis.
• -Hemodialysis and hemoperfusion can be considered
  in extremly elevated APAP level.