Acetaminophen Toxicity Dr. Peters (video) Flashcards
(25 cards)
MOA of Acetaminophen
inhibits cyclooxygenase activity
-central analgesia
-antipyretic effect
-minimal effect on inflammatory cells
What are the therapeutic doses and concentration of acetaminophen?
pediatric:
10-15 mg/kg q 4-6h, max 4g/day
adult:
650-1000 mg q 4-6h, max 4g/day
therapeutic concentration:
10-20 mcg/ml
How does a patient with Acetaminophen toxicity present?
most often:
-nausea, anorexia, malaise
severe:
-coma
-acidosis
-renal failure
-fulminant hepatic failure (in chronic ingestion)
-pancreatitis
What dose of acetaminophen is considered acute toxicity?
adults: 150 mg/kg
children <6y: 200 mg/kg
What dose of acetaminophen is considered chronic toxicity?
-200 mg/kg/day within 24 hours
-150 mg/kg/day within 48 hours
How is Acetaminophen metabolized within therapeutic doses?
by 90% through Sulfation (glutathione-dependent!!!), can become saturated and Glucuronidation
-producing non-toxic metabolites
Which metabolic pathway leads to acetaminophen toxicity?
CYP metabolism resulting in NAPQI
-NAPQI binds to cellular proteins and induces cell death (hepatotoxic)
The depletion of which molecule causes the shift to the toxic pathway?
Glutathione
What are the symptoms during Phase I and II of acetaminophen toxicity?
Phase I (12-24h after exposure):
-asymptomatic
-AMS or lactic acidosis if massive overdose
Phase II (24-36h after exposure).
-Onset of hepatotoxicity
-elevated AST (>1000IU/L)
What are the symptoms during Phase III and IV of acetaminophen toxicity?
Phase III (72-96h after exposure):
-fulminant hepatic failure
-hepatic encephalopathy, coma, hemorrhage (due to coagulopathy)
-death from MSOF (multisystem organ failure)
cerebral edema
respiratory failure
hemorrhage
Phase IV:
-complete hepatic recovery
-normal labs within 7 days, LFTs may remain elevated for several weeks
Which tool is used to assess the need for antidote therapy in acetaminophen toxicity after a single ingestion?
Rumack-Matthew Nomogram
-only after single ingestion, NOT for chronic toxicity
Which acetaminophen serum concentration 4 hours after ingestion indicates acetaminophen toxicity?
150 mcg/ml
if high-risk populations (abstinent alcoholics):100 mcg/ml
How many hours after ingestion should labs be taken to assess hepatotoxicity risk and the need for antidote treatment?
4h after ingestion
labs between 0-4h after ingestion are not conclusive
What acetaminophen concentration indicates hepatotoxicity 24 h after ingestion?
6.25 mcg/ml at 24h
-some labs don’t detect concentrations below 10 mcg/ml -> so any concentration detected is considered toxic
-elevated LFT or other biomarkers may indicate hepatotoxicity
Which labs are elevated in acetaminophen toxicity?
How many hours after ingestion are levels expected to be elevated?
-AST, ALT
(may decrease again after day 3 due to antidote or the liver has no more AST, ALT to release)
-Bilirubin (bc not metabolized in the liver)
-PT (reduction in clotting factors)
-seen between 48 to 96h -> it takes time to deplete glutathione and NAPQI to build up and cause hepatotoxicity
What are the first steps of acetaminophen toxicity management?
-manage ABC (airway, breathing, circulation)
-find out the time of ingestion (to assess antidote therapy and the right time to get acetaminophen levels)
-get labs: BMP, LFT, PT test, blood gas, acetaminophen level (after 4h!!), salicylate levels
-determine if antidote therapy is appropriate
What is the only available antidote for acetaminophen toxicity?
N-acetylcysteine (NAC)
What is the key factor for successful outcomes with NAC treatment?
time to treatment
-initiate therapy within 8 hours of ingestion
-start only if appropriate -> based on acetaminophen levels; may start without a level if they are at risk of hepatotoxicity
What is the mechanism behind the antidote therapy with NAC?
-enhance sulfation pathway (without toxic metabolite)
-acts as a glutathione precursor (increases glutathione availability)
-free radical scavenger to prevent necrosis
What is the dose of oral NAC?
What are the precautions for oral dosing?
72-hour regimen
-loading: 140 mg/kg
-maintenance: 70mg/kg q 4h -> repeat if vomit within 1 hour of administration
CAUTION: significant nausea associated with oral NAC
What is the dose for IV NAC?
21-hour regimen
loading: 150 mg/kg over 1 hour
12.5 mg/kg/hr for 4 hours (total 50 mg/kg)
6.25 mg/kg/hr for 16 hours (total 100 mg/kg)
obtain labs after 19h to assess if can stop therapy
What are the side effects associated with IV NAC dosing?
-Anaphylaxis (especially after 150 mg/kg bolus and with low acetaminophen concentration)
-> may use Benadryl, slow infusion rate, watch vital signs every 15 mins
-flushing
-N/V
-itching/scratching
When can you stop NAC?
early presenters:
-asymptomatic
-AST/ALT at baseline
-negative acetaminophen level at 19 hours (stop infusion at 21h)
late presenters:
-clinically improving
-AST/ALT have peaked already, are down trending and <1000 mc/ml
otherwise, continue with 6.25 mg/kg/hr until they meet the criteria
When should hemodialysis be considered to manage acetaminophen toxicity based on EXTRIP?
-Acetaminophen >1000mcg/mL and NAC is not given
-Acetaminophen >700mcg/mL with AMS, metabolic acidosis, and
elevated lactate AND NAC is not administered
-Acetaminophen>900mcg/mL with AMS, metabolic acidosis, and elevated lactate even IF NAC is administered (increase NAC to 12.5 mg/kg for the duration of the HD bc HD removes it from the body)
