Acetaminophen Toxicity Flashcards
What’s the therapeutics dose of acetaminophen for children and adults?
Children: 10-15mg/kg/dose q4-6h (max 80mg/kg/day) Adults: 325-1000mg q4-6h (max 4g/day)
Describe the normal hepatic metabolism of acetaminophen.
90% undergoes conjugation to either a glucuronide or a slight metabolite which are non toxic and are excreted in urine. 5% is excreted unchanged in urine. 5% is metabolized by CYP2e1 to active intermediate metabolite NAPQI which gets inactivated by conjugation w/ glutathione to non toxic metabolites and goes through renal excretion
Toxic dose of acetaminophen in acute/chronic doses for children and adults:
Acute: >7.5g (adults), >150mg/kg (children)
Chronic: >4g/day (adults), >90mg/kg/day (children)
Describe hepatotoxicity w/ acetaminophen overdose.
The amount of NAPQI produced deletes the glutathione supply (
Describe Stage I of acetaminophen toxicity.
Symptoms at 0-24hrs post ingestion.
May be asymptomatic, GI symptoms (anorexia nausea, vomiting), malaise, pallor.
Describe Stage II of acetaminophen toxicity.
Symptoms at 24-72hrs post ingestion (onset of hepatic damage).
More specific liver complaints, right upper quadrant pain, increased liver enzymes, bilirubin, coagulation & renal function decline. Maybe disappearance of symptoms from Stage I.
Describe Stage III of acetaminophen toxicity.
Symptoms at 72-96 hrs post ingestion (max hepatotoxicity).
More severe form of Stage I/II symptoms. Extreme elevations of liver enzymes, progressive hepatic encephalopathy, coagulation defects, jaundice, renal failure, myocardial necrosis, coma. (GI symptoms may return).
Describe Stage IV of acetaminophen toxicity.
Symptoms at 4 days to 2 weeks post ingestion (recovery phase).
Disappearance of clinical symptoms, normalization of lab parameters.
What AST level is considered hepatotoxic?
AST > 1000IU/L
What is the diagnostic testing for acetaminophen toxicity?
- Serum acetaminophen via Rumack Matthew Nomogram, level obtained at min of 4h post ingestion.
- Additional blood work: AST, ALT, ALP, bilirubin, PT/INR, CBC, electrolytes, urea, creatinine, glucose, ABGs.
Treat or Do Not Treat: AST > 3x ULN
Treat (regardless of serum acet.)
Treat or Do Not Treat: AST normal, serum acet detectable (>10mcg/ml)
Use clinical judgement.
Treat or Do Not Treat: AST normal, serum acet. undectable
Do not treat.
Treat or Do Not Treat: Patient presents >8h
Treat. Start NAC then re-evaluate after you get blood work.
Treat or Do Not Treat: ER Products
Use clinical judgement. Continue approach as normal.
Treat or Do Not Treat: acute EtOH + acute acet. overdose
Maybe do not treat. May be protective against acetaminophen toxicity b/c it inhibits CYP2E1 metabolism so less NAPQI formation.
Treat or Do Not Treat: chronic EtOH + acute acet. overdose
Treat. Patient at higher risk of toxicity b/c of increased CYP2E1 activity and decreased glutathione stores.
Treat or Do Not Treat: chronic EtOH + chronic acet. ingestion
Do not treat if patient not consuming >4g/day on regular basis.
What pre-existing conditions cause an increased risk of toxicity w/ repeated excessive doses?
Febrile infants, chronic EtOH consumption, concurrent CYP inducers.
What effect do CYP inducers have on acetaminophen toxicity?
Could worsen outcomes and increase toxicity b/c since more acetaminophen is metabolized by the CYP pathway, there’s more NAPQI production.
What effect does chronic liver disease in a non-alcohol user have on acetaminophen toxicity?
No increased risk of toxicity b/c though elimination half life go acetaminophen is longer, CYP activity is low so little/low NAPQI production.
What are the mechanisms of action of NAC?
- Augmenting sulfation.
- Acting as a glutathione precursor.
- Acting as a glutathione substitute.
- Modifying the secondary effects of the inflammatory response after the initial direct toxic injury.
NAC Oral Dosing:
Loading dose (240mg/kg) diluted to 5%, then 70mg/kg q4h for 17 doses = 72 hours total.
NAC IV Dosing:
150 mg/kg in 200ml D5W over 60 min, then 50mg/kg in 500ml over 4 hours, then 100mg/kg in 1000ml over 16 hours = 21 hours total.
Advantages of IV NAC Route:
- Allows for concomitant administration of charcoal & NAC without the risk of NAC adsorption to the charcoal.
- Decreased risk of vomiting.
- Administered over a shorter period of time (21h vs 72h)
- Easier to administer to those w/ altered LOC.
Advantages of Oral NAC Route:
- Doesn’t require IV access.
- No reports of life threatening adverse effects.
- NAC delivered directly to liver.
When is IV NAC route preferred?
Pregnancy, liver failure, severe vomiting, contraindication to oral administration.
ADRs for IV NAC:
Anaphylactoid reaction - rash, pruritus, flushing, angioedema, hypotension.
ADRs for oral NAC:
GI - nausea, vomiting, reflux, diarrhea.
When is hemodialysis appropriate in acetaminophen toxicity?
When massive ingestions w/ very high levels ( >1000mg/L) complicated by coma and/or hypotension.
When is liver transplantation considered in acetaminophen toxicity?
- Arterial pH 3mmol/L after fluid resuscitation.
2. SCr > 3.3mg/dL, PT > 100sec or INR >6.5, Grade III or IV encephalopathy
What is the supportive management in acetaminophen toxicity?
- Coagulopathy: vitamin K, FFP, prothrombin complex concentrates
- Cerebral edema: fluid retention, mannitol
- Nausea/Vomiting: dimenhydrinate
- Hypoglycemia: dextrose
What do you monitor for in acetaminophen toxicity?
- Bloodwork: LFTs (esp AST), INR, bicarbonate, SCr q12h, daily electrolytes
- Clinical status: HR, BP, LOC, temp
