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PHAR324 > Acetaminophen Toxicity > Flashcards

Acetaminophen Toxicity Flashcards

1
Q

What is the second most common cause of liver transplantation worldwide?

A

acetaminophen toxicity

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2
Q

What is the reason for acetaminophens very poor anti-inflammatory action?

A

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)

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3
Q

What are the proposed MOAs of acetaminophen?

A

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

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4
Q

Describe the PK of acetaminophen.

A

absorption:
-well absorbed
distribution:
-1/4th is protein bound in plasma
-uniformly distributed
metabolism:
-phase I: glucuronidation and sulphation
-excreted
-CYP –> NAPQI

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5
Q

What is the problem with NAPQI?

A

free NAPQI is highly toxic due to its high reactivity with -SH groups present in DNA, RNA, and proteins

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6
Q

What causes neutralization of NAPQI?

A

reacts with glutathione in liver which neutralizes to non-toxic metabolite

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7
Q

What is the mechanism of NAPQI toxicity?

A

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

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8
Q

Which products resulted in the most acetaminophen overdoses?

A

single product (66%)
-Rx opioid combo = 21%
-OTC cough and cold = 10%

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9
Q

What is the Vd of acetaminophen?

A

0.7-1.2 L/kg

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10
Q

How much of acetaminophen is plasma protein bound?

A

10-25%

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11
Q

Describe metabolism of acetaminophen under normal conditions.

A

85-90% metabolized in liver
-30% sulfation
-55% glucuronidation
-5-10% CYP 2E1/3A4/1A2
5% excreted unchanged in urine

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12
Q

What is the risk of acetaminophen in chronic alcoholics?

A

alcohol causes liver disease –> glutathione levels decrease
alcohol stimulates CYP –> increased NAPQI

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13
Q

What are the possible explanations for why young children have increased tolerance to higher doses of acetaminophen?

A

increased capacity of sulfation pathways
increased glutathione stores
increase propensity to vomit post-ingestion
immature CYP 2E1

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14
Q

What are the toxic doses of acetaminophen?

A

single dose adults:
- > 12 g or 150 mg/kg
single dose pediatrics:
- > 150 mg/kg (200 mg/kg in healthy children aged 1-6)

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15
Q

Which populations are at risk of acetaminophen toxicity?

A

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

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16
Q

What are some non-hepatic toxicities of acetaminophen?

A

renal failure
-kidneys also metabolize acetaminophen ton toxic metabolite
myocardial necrosis

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17
Q

Describe phase 1 of acute acetaminophen toxicity.

A

0-24h
-vomiting
-nausea
-anorexia
-diaphoresis

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18
Q

Describe phase 2 of acute acetaminophen toxicity.

A

18-72h
-reduction in symptoms from phase 1
-increase liver enzymes (ALT, AST)
-hepatic failure (death of hepatocytes)
-RUQ pain

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19
Q

Describe phase 3 of acute acetaminophen toxicity.

A

72-96h
-hepatitis is acute in onset, progresses rapidly
-elevation of plasma aminotransferases
-rising PT/INR (longer to clot)

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20
Q

Describe phase 4 of acute acetaminophen toxicity.

A

4 days to 3 weeks
-assuming they are coming around
-complete resolution of sx
-return to baseline liver enzyme levels
-no chronic hepatic dysfunction

21
Q

What is the first step in acute acetaminophen toxicity?

A

ABCs and supportive care

22
Q

What are important pieces of information to gather for acetaminophen toxicity?

A

*time of ingestion
*product ingested (dosage form)

23
Q

What is the most important diagnostic tool for acetaminophen toxicity?

A

plasma level

24
Q

How is hepatoxicity best predicted in acetaminophen toxicity?

A

by relating time of ingestion to serum acetaminophen concentrations

25
Q

What is the relationship between amount of acetaminophen ingested and plasma concentration?

A

poor correlation

26
Q

How long do we wait before taking acetaminophen levels?

A

4 hours
-tmax=4h

27
Q

What is the tool for predicting hepatoxicity of acetaminophen overdose?

A

Rumack-Matthew nomogram
-at 4 hours single oral dose
-25% difference to take into account possible lab error

28
Q

What are limitations to Rumack-Matthew nomogram?

A

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

29
Q

What is the role of decontamination in acetaminophen overdose?

A

no role for ipecac or gastric lavage
SDAC
-may reduce absorption is administered within 1h post ingestion or more in case of MR products

30
Q

What is the role of elimination in acetaminophen toxicity?

A

MDAC
-no role
acetaminophen neither an acid or base
-no role for alkalinization or acification

31
Q

What are characteristics that make a drug a good candidate for hemodialysis?

A

low/no protein binding
low Vd (<1L/kg)
water soluble
< 500 Dalton

32
Q

What is the role of hemodialysis for acetaminophen toxicity?

A

will remove acetaminophen from plasma but hasnt been shown to prevent hepatotoxicity

33
Q

What is the MOA of NAC?

A

numerous proposed theories:
-maintains glutathione levels
-promotes formation of sulfate conjugate
-antioxidant properties
-improved hepatic blood flow & O2 deliver
replenishes glutathione stores in liver

34
Q

What are the indications for NAC?

A

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

35
Q

What is the benefit of NAC during different time frames?

A

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

36
Q

When do we stop NAC?

A

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

37
Q

What is the issue with oral NAC?

A

smells like rotten eggs

38
Q

What are non-immunologic anaphylactic reactions to NAC?

A

cutaneous: flushing, pruritis, erythema
systemic: cough, SOB, wheezing, hypotension

39
Q

How do we manage non-immunologic anaphylactic reactions to NAC?

A

stop infusion
IV antihistamines
symptomatic care
continue infusion at slower rate

40
Q

What should be done for acetaminophen toxicity during the 0-4h window?

A

consider SDAC if within 1-2h
draw samples for lab tests
wait until 4h post-ingestion to draw sample for plasma acetaminophen

41
Q

What should be done for acetaminophen toxicity during the 4-8h window?

A

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

42
Q

What should be done for acetaminophen toxicity during the 8-24h window?

A

draw samples
start NAC
once plasma acetaminophen results back, continue as 4-8h, except continue NAC if ALT > 50 IU/L

43
Q

What should be done for acetaminophen toxicity during the >24h window?

A

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

44
Q

Which population is repeated supratherapeutic toxicity most common in?

A

young adults
-repeated ingestion associated with greater risk of hepatotoxicity and mortality than single dose

45
Q

What is the use of the nomogram for repeated supratherapeutic dose?

A

not helpful

46
Q

What is the role of decontamination for repeated supratherapeutic toxicity?

A

usually not a priority
no ipecac or lavage
SDAC may be warranted if recent large dose

47
Q

What is the role of elimination for repeated supratherapeutic toxicity?

A

no methods of benefit

48
Q

What is the role of the nomogram for extended release acetaminophen?

A

questioned

49
Q

What is the protocol for extended release acetaminophen overdose?

A

SDAC if within 4h ingestion

PHAR324 (9 decks)

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