Acetaminophen Toxicity Dr. Peters (video) Flashcards
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)
What is the King’s College criteria?
scoring tool to identify patients who should be recommended immediately for liver transplantation
-arterial pH < 7.3
-INR > 6.5
-Creatinine > 3.4 mg/dl
-Grade III or IV hepatic encephalopathy
-lactate > 3.5 after fluid resuscitation within 4 hours
or 3 mmol/l after full resuscitation
-Phosphate > 3.75 mg/dl at 48-96h
