Acetaminophen

Question 1

How is acetaminophen metabolized?

Answer 1

Hepatic conjugation (90%):
- Glucuronidation (40-67%)
- Sulfation (20-46%)
Renal excretion (5%)
Oxidation by CYP (5-15%)
- NAPQI formation
- NAPQI rapidly combined with glutathione
- NAPQI-glutathione convereted to non-toxic cysteine or mercaptate conjugates
Eliminated in urine

Question 2

How does NAC reduce APAP toxicity?

Answer 2

• Prevents toxicity by limiting NAPQI formation
  o Increases sulfation pathway of APAP by acting as a sulfur containing glutathioone substitute
• Increases the capacity to detoxify NAPQI
  o Acts as glutathione precursor, increasing glutathione availability
  o Acts as a substitute for glutathione, combining directly with NAC
  o Reduces NAPQI back to APAP
• Treats hepatotoxicity:
  o Free radical scavenger
  o Antioxidant
  o Alters hepatic microcirculation and O2 delivery
  o Increases PMNs in liver
• Reduces end organ dysfunction:
  o Decreases cerebral edema, hypotension, and death when no APAP remains

Question 3

List the stages of acetaminophen induced hepatic toxicity.

Answer 3

Stage 1: Pre-injury LT24 hours
- +/- Nausea and vomiting in the first 8 hours
- high APAP levels, normal LFTs

Stage 2: Onset of liver injury 8-36 hours
Sign and symptoms of hepatic injury:
- Nausea, vomiting, epigastric/RUQ pain and tenderness
- Transaminitis: AST most SN, starts ~ 8hrs
- Hepatotoxicity = AST >1000
- high bili, PTT, ALT, peak shortly after AST
Stage 3: Fulminant Liver failure 2-4 days
- Fulminant liver failure
- Encephalopathy, coma, coagulopathy, hypoglycemia, metabiolic acidosis, hemorrhage
- ALT,AST GT10,000
- abnormal PTT, bili, glucose, lactate, pH, phosphate prognostic factors
- Death can occur secondary to: Hemorrhage, ARDS, sepsis, MOD, cerebral edema

Stage 4: Recovery period GT 4 days
- Hepatic enzymes return to baseline
- Histologic resolution can take months
- Regeneration of the liver is complete without chronic hepatic dysfunction

Question 4

What is the lowest acute dose capable of causing toxicity?

Answer 4

• Adults: 7.5g
• Children 150mg/kg
• ONLY if reliable history!! Otherwise be conservative and get levels.

Question 5

What is the time fram for starting NAC?

Answer 5

6-8hrs after start of ingrdyion

Question 6

List factors that may predispose patients to injury from chronic acetaminophen exposure.

Answer 6

Depletion of glutathione
- Malnourishment
- Chronic alcohol use
- HIV/AIDS
- Chronic disease
Induction of P450
- Chronic Alcohol use
- Medications:
	· Isonizid
	· Anticonvulsants (Dilantin, tegretol, phenobarb)
- Febrile illness in child <5 years old
- Smoking

Question 7

What are the 4 principles of management of acetaminophen toxicity?

Answer 7

1. Limit gastrointestinal absorption when appropriate
   
   2. Initiate NAC therapy in a timely manner, within 8 hours of ingestion
   3. Control symptoms
      Provide supportive and follow-up care

Question 8

List the King’s college criteria

Answer 8

• pH <7.3 after fluid resuscitation
• OR combined endpoint of:
  · Creatinine >300 and
  · INR >5 (PTT >100) and
  · Encephalopathy > grade III (comatose)
• Developed and validated on patients with APAP induced hepatic failure.
• Predicts the need for transplant, and survival of ~20% without transplant