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Year 4 - Toxicology > 4 - Acetaminophen > Flashcards

4 - Acetaminophen Flashcards

1
Q

Describe acetaminophen absorption

A
  • Rapid, almost complete w/in 2 h (must be very soon after ingestion if want to use gastric emptying as tx option)
  • Peak levels at 30-120 min (w/in 4 h)
  • BA = 60-98%
  • First-pass metabolism = 25%
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2
Q

Describe distribution of acetaminophen

A
  • Vd = 0.8-1 L/kg (low, mostly in the bloodstream and can reach target site quickly)
  • Protein binding = 10-30%
  • Crosses placenta and BBB
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3
Q

Describe acetaminophen elimination

A
  • Liver metabolism
  • 5% urinary excretion
  • < 2% of maternal dose enters breast milk
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4
Q

What is the half life of acetaminophen?

A
  • t1/2 = 1-3 h (at therapeutic doses)

* *t1/2 > 12 h in OD

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5
Q

Toxic dose of acetaminophen

A

6-7 g in adults (w/o risk factors); > 140 mg/kg in children (lower P450 metabolism)

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6
Q

What is a “danger” plasma level (4-hour action level)?

A

> / 150 ug/mL

**Always need to ask for levels b/c toxicity doesn’t occur immediately

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7
Q

Describe the hepatic toxicity in acetaminophen overdose

A
  • Saturation of glucuronide and sulfate conjugation pathways
  • Shunting of APAP into P450 system (NAPQI)
  • Glutathione (GSH) depletion
  • NAPQI binds and arylates cell proteins => cell death (DNA fragmentation, mitochondrial injury)
  • Inflammation after necrosis => impaired microcirculation => tissue hypoxia
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8
Q

Describe renal toxicity of acetaminophen

A

Acute proximal renal tubular necrosis (renal P450 formation of NAPQI)

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9
Q

How many phases of acetaminophen overdose are there?

A

4

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10
Q

Describe phase 1 of acetaminophen overdose

A
  • 0.5 – 24 h

- No sx or non-specific sx (anorexia, nausea or vomiting, malaise, diaphoresis)

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11
Q

Describe phase 2 of acetaminophen overdose

A
  • 24 - 72 h

- Abdominal pain, liver tenderness, elevated AST and ALT, elevated bilirubin, metabolic acidosis hypoglycemia

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12
Q

Describe phase 3 of acetaminophen overdose

A
  • 72 - 96 h
  • Hepatic encephalopathy, continuing rise in PT, coagulopathy, fulminant hepatic failure, acute renal failure
  • If pt has not received tx at this point, always get the levels to assess how much is still in the system
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13
Q

Describe phase 4 of acetaminophen overdose

A
  • 4 days to 2 weeks

- Resolution of hepatic dysfunction (if pt survived phase 3)

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14
Q

Management of acetaminophen overdose

A
  • Lab tests
    • Routine acetaminophen levels in all OD px
    • 4-h post ingestion levels (use nomogram to predict toxicity)
  • Early diagnosis important
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15
Q

Intervention options for acetaminophen overdose

A
  • Gastric emptying
  • Activated charcoal
  • N-acetylcysteine (NAC)
  • Supportive care
  • Liver transplant
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16
Q

When would you use gastric emptying for acetaminophen overdose?

A
  • Very early presentation (< 1 hour)
  • Ingestion of sustained-release formulations
  • Co-ingestion of agents that delay absorption
17
Q

How can N-acetylcysteine be administered?

A
  • PO and IV
  • Foul smelling/ tasting and irritating to stomach, so PO administration w/ orange/ grapefruit juice or soda and antiemetics
  • Rapid IV administration can cause flushing, hypotension, and bronchoconstriction (anaphylactoid reactions)
18
Q

When is N-acetylcysteine most effective?

A

If administered within 8-10 hours of APAP ingestion

19
Q

Is N-acetylcysteine safe in pregnancy?

A

Appears to be

20
Q

NAC mechanism of action

A
  • Precursor of synthesis of glutathione and sulfate (prevents depletion)
  • Direct binding to NAPQI (GSH substitute)
  • Modulation of cascade of inflammatory events
  • Non-specific antioxidant effects and mediation of microvascular tone = improved organ function
21
Q

NAC indications

A
  • Serum concentration at 4 hours or more following acute ingestion of immediate-release preparation is above the “treatment” line of nomogram
  • Suspected single ingestion of > 150 mg/kg (7.5 g total dose regardless of weight)
  • Pt w/ unknown time of ingestion and serum concentration > 10 mcg/mL (66 micromole/L)
  • Pt w/ hx of ingestion and any evidence of liver injury
  • Pt w/ delayed presentation (> 24 h after ingestion) w/ lab evidence of liver injury (from mildly elevated aminotransferases to fulminant hepatic failure)
22
Q

NAC dose (Canada)

A

IV NAC for 20 hours (150 mg/kg over 15 minutes, 50 mg/kg over 4 hours, 100 mg/kg over 16 hours)

23
Q

What is considered chronic acetaminophen toxicity?

A
  • Daily consumption of supra-therapeutic doses (> 4-6 g/day) by alcoholic px
  • Children = 60-150 mg/kg/day for 2-8 days
24
Q

Treatment of chronic acetaminophen toxicity?

A

Treatment w/ NAC if liver enzymes elevated or high-risk px

25
Q

Risk factors for chronic acetaminophen toxicity

A
  • Alcoholism
  • Chronic tx w/ anticonvulsants or isoniazid
  • Fasting and malnutrition

Year 4 - Toxicology (22 decks)

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