4 - Acetaminophen Flashcards
Describe acetaminophen absorption
- Rapid, almost complete w/in 2 h (must be very soon after ingestion if want to use gastric emptying as tx option)
- Peak levels at 30-120 min (w/in 4 h)
- BA = 60-98%
- First-pass metabolism = 25%
Describe distribution of acetaminophen
- Vd = 0.8-1 L/kg (low, mostly in the bloodstream and can reach target site quickly)
- Protein binding = 10-30%
- Crosses placenta and BBB
Describe acetaminophen elimination
- Liver metabolism
- 5% urinary excretion
- < 2% of maternal dose enters breast milk
What is the half life of acetaminophen?
- t1/2 = 1-3 h (at therapeutic doses)
* *t1/2 > 12 h in OD
Toxic dose of acetaminophen
6-7 g in adults (w/o risk factors); > 140 mg/kg in children (lower P450 metabolism)
What is a “danger” plasma level (4-hour action level)?
> / 150 ug/mL
**Always need to ask for levels b/c toxicity doesn’t occur immediately
Describe the hepatic toxicity in acetaminophen overdose
- Saturation of glucuronide and sulfate conjugation pathways
- Shunting of APAP into P450 system (NAPQI)
- Glutathione (GSH) depletion
- NAPQI binds and arylates cell proteins => cell death (DNA fragmentation, mitochondrial injury)
- Inflammation after necrosis => impaired microcirculation => tissue hypoxia
Describe renal toxicity of acetaminophen
Acute proximal renal tubular necrosis (renal P450 formation of NAPQI)
How many phases of acetaminophen overdose are there?
4
Describe phase 1 of acetaminophen overdose
- 0.5 – 24 h
- No sx or non-specific sx (anorexia, nausea or vomiting, malaise, diaphoresis)
Describe phase 2 of acetaminophen overdose
- 24 - 72 h
- Abdominal pain, liver tenderness, elevated AST and ALT, elevated bilirubin, metabolic acidosis hypoglycemia
Describe phase 3 of acetaminophen overdose
- 72 - 96 h
- Hepatic encephalopathy, continuing rise in PT, coagulopathy, fulminant hepatic failure, acute renal failure
- If pt has not received tx at this point, always get the levels to assess how much is still in the system
Describe phase 4 of acetaminophen overdose
- 4 days to 2 weeks
- Resolution of hepatic dysfunction (if pt survived phase 3)
Management of acetaminophen overdose
- Lab tests
- Routine acetaminophen levels in all OD px
- 4-h post ingestion levels (use nomogram to predict toxicity)
- Early diagnosis important
Intervention options for acetaminophen overdose
- Gastric emptying
- Activated charcoal
- N-acetylcysteine (NAC)
- Supportive care
- Liver transplant
When would you use gastric emptying for acetaminophen overdose?
- Very early presentation (< 1 hour)
- Ingestion of sustained-release formulations
- Co-ingestion of agents that delay absorption
How can N-acetylcysteine be administered?
- PO and IV
- Foul smelling/ tasting and irritating to stomach, so PO administration w/ orange/ grapefruit juice or soda and antiemetics
- Rapid IV administration can cause flushing, hypotension, and bronchoconstriction (anaphylactoid reactions)
When is N-acetylcysteine most effective?
If administered within 8-10 hours of APAP ingestion
Is N-acetylcysteine safe in pregnancy?
Appears to be
NAC mechanism of action
- Precursor of synthesis of glutathione and sulfate (prevents depletion)
- Direct binding to NAPQI (GSH substitute)
- Modulation of cascade of inflammatory events
- Non-specific antioxidant effects and mediation of microvascular tone = improved organ function
NAC indications
- Serum concentration at 4 hours or more following acute ingestion of immediate-release preparation is above the “treatment” line of nomogram
- Suspected single ingestion of > 150 mg/kg (7.5 g total dose regardless of weight)
- Pt w/ unknown time of ingestion and serum concentration > 10 mcg/mL (66 micromole/L)
- Pt w/ hx of ingestion and any evidence of liver injury
- Pt w/ delayed presentation (> 24 h after ingestion) w/ lab evidence of liver injury (from mildly elevated aminotransferases to fulminant hepatic failure)
NAC dose (Canada)
IV NAC for 20 hours (150 mg/kg over 15 minutes, 50 mg/kg over 4 hours, 100 mg/kg over 16 hours)
What is considered chronic acetaminophen toxicity?
- Daily consumption of supra-therapeutic doses (> 4-6 g/day) by alcoholic px
- Children = 60-150 mg/kg/day for 2-8 days
Treatment of chronic acetaminophen toxicity?
Treatment w/ NAC if liver enzymes elevated or high-risk px
