Acetaminophen Toxicity Flashcards
What is the second most common cause of liver transplantation worldwide?
acetaminophen toxicity
What is the reason for acetaminophens very poor anti-inflammatory action?
peroxide theory:
-Tylenol becomes inactive in presence of peroxide
-peroxide is present in large amounts at site of inflammation
COX-3 inhibitor theory:
-Tylenol inhibits COX-3 but not COX-1 or COX-2
-COX-3 is present in the brain (controls fever and pain)
What are the proposed MOAs of acetaminophen?
reversibly inhibits COX pathways in CNS
decreases production of PGs
decrease in PG stimulates nociceptive neurons and hypothalamus –> relives pain and fever
exact MOA remains unclear
Describe the PK of acetaminophen.
absorption:
-well absorbed
distribution:
-1/4th is protein bound in plasma
-uniformly distributed
metabolism:
-phase I: glucuronidation and sulphation
-excreted
-CYP –> NAPQI
What is the problem with NAPQI?
free NAPQI is highly toxic due to its high reactivity with -SH groups present in DNA, RNA, and proteins
What causes neutralization of NAPQI?
reacts with glutathione in liver which neutralizes to non-toxic metabolite
What is the mechanism of NAPQI toxicity?
mechanism of hepatocyte death via active metabolite:
-forms covalent bonds with vital proteins, lipid bilayers, killing cells
-creates reactive O2 species (ROS)
-decreases glutathione and cytosolic thiols
-loss of mitochondrial membrane potential
it causes necrosis in liver cells and kidney tubules
Which products resulted in the most acetaminophen overdoses?
single product (66%)
-Rx opioid combo = 21%
-OTC cough and cold = 10%
What is the Vd of acetaminophen?
0.7-1.2 L/kg
How much of acetaminophen is plasma protein bound?
10-25%
Describe metabolism of acetaminophen under normal conditions.
85-90% metabolized in liver
-30% sulfation
-55% glucuronidation
-5-10% CYP 2E1/3A4/1A2
5% excreted unchanged in urine
What is the risk of acetaminophen in chronic alcoholics?
alcohol causes liver disease –> glutathione levels decrease
alcohol stimulates CYP –> increased NAPQI
What are the possible explanations for why young children have increased tolerance to higher doses of acetaminophen?
increased capacity of sulfation pathways
increased glutathione stores
increase propensity to vomit post-ingestion
immature CYP 2E1
What are the toxic doses of acetaminophen?
single dose adults:
- > 12 g or 150 mg/kg
single dose pediatrics:
- > 150 mg/kg (200 mg/kg in healthy children aged 1-6)
Which populations are at risk of acetaminophen toxicity?
those with decreased glutathione stores
-chronic alcohol consumption
-fasting and malnutrition: depletes glycogen stores
concomitant enzyme-inducing drugs
-chronic alcohol, isoniazid, phenobarb, primidone, SJW
chronic liver disease, NAFLD, hepatitis
What are some non-hepatic toxicities of acetaminophen?
renal failure
-kidneys also metabolize acetaminophen ton toxic metabolite
myocardial necrosis
Describe phase 1 of acute acetaminophen toxicity.
0-24h
-vomiting
-nausea
-anorexia
-diaphoresis
Describe phase 2 of acute acetaminophen toxicity.
18-72h
-reduction in symptoms from phase 1
-increase liver enzymes (ALT, AST)
-hepatic failure (death of hepatocytes)
-RUQ pain
Describe phase 3 of acute acetaminophen toxicity.
72-96h
-hepatitis is acute in onset, progresses rapidly
-elevation of plasma aminotransferases
-rising PT/INR (longer to clot)
Describe phase 4 of acute acetaminophen toxicity.
4 days to 3 weeks
-assuming they are coming around
-complete resolution of sx
-return to baseline liver enzyme levels
-no chronic hepatic dysfunction
What is the first step in acute acetaminophen toxicity?
ABCs and supportive care
What are important pieces of information to gather for acetaminophen toxicity?
*time of ingestion
*product ingested (dosage form)
What is the most important diagnostic tool for acetaminophen toxicity?
plasma level
How is hepatoxicity best predicted in acetaminophen toxicity?
by relating time of ingestion to serum acetaminophen concentrations
What is the relationship between amount of acetaminophen ingested and plasma concentration?
poor correlation
How long do we wait before taking acetaminophen levels?
4 hours
-tmax=4h
What is the tool for predicting hepatoxicity of acetaminophen overdose?
Rumack-Matthew nomogram
-at 4 hours single oral dose
-25% difference to take into account possible lab error
What are limitations to Rumack-Matthew nomogram?
patients presenting late (>24h)
chronic/repeated supratherapeutic ingestion
MR products - absorbed at different rates
time of ingestion estimate liable to be inaccurate
-altered mental status
at-risk populations
What is the role of decontamination in acetaminophen overdose?
no role for ipecac or gastric lavage
SDAC
-may reduce absorption is administered within 1h post ingestion or more in case of MR products
What is the role of elimination in acetaminophen toxicity?
MDAC
-no role
acetaminophen neither an acid or base
-no role for alkalinization or acification
What are characteristics that make a drug a good candidate for hemodialysis?
low/no protein binding
low Vd (<1L/kg)
water soluble
< 500 Dalton
What is the role of hemodialysis for acetaminophen toxicity?
will remove acetaminophen from plasma but hasnt been shown to prevent hepatotoxicity
What is the MOA of NAC?
numerous proposed theories:
-maintains glutathione levels
-promotes formation of sulfate conjugate
-antioxidant properties
-improved hepatic blood flow & O2 deliver
replenishes glutathione stores in liver
What are the indications for NAC?
plasma acetaminophen at or above possible hepatoxicity on nomogram
late presenting patients with symptoms of hepatic damage
repeated supratherapeutic with increased liver enzymes
fulminant hepatic failure
?? at-risk patients with other signs/sx of toxicity incongruent with nomogram result
What is the benefit of NAC during different time frames?
0-4h:
-generally will not administer during this time
4-8h:
-benefit equal throughout this period
-though toxicity does not occur until glutathione levls < 30% (takes about 8 hours)
8-24h:
-still effective, though benefit wanes with each passing 4h block
>24h:
-not clear
When do we stop NAC?
not just duration
stop NAC at end of regimen (IV 21h) or satisfaction of all below:
-ALT/AST normal or declining
-undetectable acetaminophen in plasma
-no coagulopathy
-SCr normal or declining
-clinically well
What is the issue with oral NAC?
smells like rotten eggs
What are non-immunologic anaphylactic reactions to NAC?
cutaneous: flushing, pruritis, erythema
systemic: cough, SOB, wheezing, hypotension
How do we manage non-immunologic anaphylactic reactions to NAC?
stop infusion
IV antihistamines
symptomatic care
continue infusion at slower rate
What should be done for acetaminophen toxicity during the 0-4h window?
consider SDAC if within 1-2h
draw samples for lab tests
wait until 4h post-ingestion to draw sample for plasma acetaminophen
What should be done for acetaminophen toxicity during the 4-8h window?
draw samples for lab tests
at or above possible hepatotoxicity
-IV NAC until 21h or until all endpoints met
-if patient is not NV/RUQ and normal labs=discharge
-seek medical attention if sx develop
What should be done for acetaminophen toxicity during the 8-24h window?
draw samples
start NAC
once plasma acetaminophen results back, continue as 4-8h, except continue NAC if ALT > 50 IU/L
What should be done for acetaminophen toxicity during the >24h window?
no established guideline
the earlier NAC initiated, the more effectively it will be in preventing hepatoxicity
start NAC
-continue if ALT > 50 IU/L
-reassess q12h; continue until ALT < 50 IU/L
Which population is repeated supratherapeutic toxicity most common in?
young adults
-repeated ingestion associated with greater risk of hepatotoxicity and mortality than single dose
What is the use of the nomogram for repeated supratherapeutic dose?
not helpful
What is the role of decontamination for repeated supratherapeutic toxicity?
usually not a priority
no ipecac or lavage
SDAC may be warranted if recent large dose
What is the role of elimination for repeated supratherapeutic toxicity?
no methods of benefit
What is the role of the nomogram for extended release acetaminophen?
questioned
What is the protocol for extended release acetaminophen overdose?
SDAC if within 4h ingestion
