Lecture 5 - Acetaminophen Flashcards
Describe the absorption of acetaminophen
Rapid, almost complete within 2 hours
When does acetaminophen peak?
peak levels at 30-120 min (within 4 hours)
T or F: acetaminophen crosses placenta
true
*but normal doses in pregnancy is safe
T or F: does not cross BBB
false - it does cross BBB
Describe the liver metabolism of acetaminophen
90% conjugation
- glucuronic acid
- sulfate
3-8% oxidation
-N-acetyl-p-benzoquinoneimine, NAPQI (toxic metabolite - glutathione conjugation)
How much acetaminophen is eliminated through urinary excretion?
<5%
Acetaminophen in breast milk?
<2% of maternal dose
Half life of acetaminophen at normal doses and OD
1-3 hours (at therapeutic doses)
> 12 hours in OD
What is toxic dose of acetaminophen
6-7 g in adults
>140mg/kg in children
Children have a ____ P450 metabolism so they can tolerate more
lower
Describe the acute hepatic toxicity of acetaminophen in OD
- Saturation of glucuronide and sulphate conjugation pathways
- Shunting of APAP into the P450 system (NAPQI)
- Glutathione (GSH) depletion
- NAPQI binds and acylates cell proteins (irreversible?) - and can cause cell death
- Inflammation after necrosis (centrilubular).
- Impaired microcirculation = tissue hypoxia
Describe the acute renal toxicity of acetaminophen in OD
acute proximal renal tubular necrosis (renal P450 formation of NAPQI)
Describe Phase 1 toxicity
No symptoms or non-specific symptoms (anorexia, nausea, or vomiting, malaise, diaphoresis)
What time does phase 1 toxicity happen?
0.5h - 24h
Describe Phase 2 toxicity
- abdominal pain
- liver tenderness
- elevated liver enzymes (AST and ALT)
- elevated bilirubin
- metabolic acidosis
- hypoglycemia
What time does phase 2 toxicity happen?
24-72h
Describe Phase 3 toxicity
- Hepatic encephalopathy
- Continuing rise in PT
- Coagulopathy (bleeding disorder)
- Fulminant hepatic failure
- Acute renal failure
What time does phase 3 toxicity happen?
72-96h
Describe Phase 4 toxicity
Resolution of hepatic dysfunction (if patient survived phase 3)
What time does phase 4 toxicity happen?
4 days - 2 weeks
What is the management for acetaminophen toxicity?
1) Lab tests! (always order plasma acetaminophen levels and liver enzymes)
2) Early diagnosis is important
- Routine acetaminophen levels in all overdosed patients
- 4-hour post-ingestion levels (use of the nomogram to predict toxicity)
What are some interventions for acetaminophen toxicity?
- Gastric emptying
- AC
- N-acetylcysteine (NAC) which is the antidote
- Supportive care
- Liver transplant (last resort)
When is gastric emptying appropriate for acetaminophen toxicity?
- Very early presentation (<1 hour)
- Ingestion of SR formulations
- Co-ingestion of agents that delay absorption
When is activated charcoal appropriate for acetaminophen toxicity?
- Concerns regarding oral administration of NAC (if you administer NAC and AC together, the NAC will be absorbed by AC)
- GI absorption generally complete after 4 hours (delayed absorption?)
- Concomitant ingestions? (AC may still be useful for other agents that may be present)