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Year 4 - Toxicology > Lecture 5 - Acetaminophen > Flashcards

Lecture 5 - Acetaminophen Flashcards

1
Q

Describe the absorption of acetaminophen

A

Rapid, almost complete within 2 hours

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2
Q

When does acetaminophen peak?

A

peak levels at 30-120 min (within 4 hours)

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3
Q

T or F: acetaminophen crosses placenta

A

true

*but normal doses in pregnancy is safe

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4
Q

T or F: does not cross BBB

A

false - it does cross BBB

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5
Q

Describe the liver metabolism of acetaminophen

A

90% conjugation

  • glucuronic acid
  • sulfate

3-8% oxidation
-N-acetyl-p-benzoquinoneimine, NAPQI (toxic metabolite - glutathione conjugation)

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6
Q

How much acetaminophen is eliminated through urinary excretion?

A

<5%

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7
Q

Acetaminophen in breast milk?

A

<2% of maternal dose

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8
Q

Half life of acetaminophen at normal doses and OD

A

1-3 hours (at therapeutic doses)

> 12 hours in OD

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9
Q

What is toxic dose of acetaminophen

A

6-7 g in adults

>140mg/kg in children

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10
Q

Children have a ____ P450 metabolism so they can tolerate more

A

lower

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11
Q

Describe the acute hepatic toxicity of acetaminophen in OD

A
  • Saturation of glucuronide and sulphate conjugation pathways
  • Shunting of APAP into the P450 system (NAPQI)
  • Glutathione (GSH) depletion
  • NAPQI binds and acylates cell proteins (irreversible?) - and can cause cell death
  • Inflammation after necrosis (centrilubular).
  • Impaired microcirculation = tissue hypoxia
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12
Q

Describe the acute renal toxicity of acetaminophen in OD

A

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

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13
Q

Describe Phase 1 toxicity

A

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

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14
Q

What time does phase 1 toxicity happen?

A

0.5h - 24h

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15
Q

Describe Phase 2 toxicity

A
  • abdominal pain
  • liver tenderness
  • elevated liver enzymes (AST and ALT)
  • elevated bilirubin
  • metabolic acidosis
  • hypoglycemia
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16
Q

What time does phase 2 toxicity happen?

A

24-72h

17
Q

Describe Phase 3 toxicity

A
  • Hepatic encephalopathy
  • Continuing rise in PT
  • Coagulopathy (bleeding disorder)
  • Fulminant hepatic failure
  • Acute renal failure
18
Q

What time does phase 3 toxicity happen?

A

72-96h

19
Q

Describe Phase 4 toxicity

A

Resolution of hepatic dysfunction (if patient survived phase 3)

20
Q

What time does phase 4 toxicity happen?

A

4 days - 2 weeks

21
Q

What is the management for acetaminophen toxicity?

A

1) Lab tests! (always order plasma acetaminophen levels and liver enzymes)

2) Early diagnosis is important
- Routine acetaminophen levels in all overdosed patients
- 4-hour post-ingestion levels (use of the nomogram to predict toxicity)

22
Q

What are some interventions for acetaminophen toxicity?

A
  • Gastric emptying
  • AC
  • N-acetylcysteine (NAC) which is the antidote
  • Supportive care
  • Liver transplant (last resort)
23
Q

When is gastric emptying appropriate for acetaminophen toxicity?

A
  • Very early presentation (<1 hour)
  • Ingestion of SR formulations
  • Co-ingestion of agents that delay absorption
24
Q

When is activated charcoal appropriate for acetaminophen toxicity?

A
  • Concerns regarding oral administration of NAC (if you administer NAC and AC together, the NAC will be absorbed by AC)
  • GI absorption generally complete after 4 hours (delayed absorption?)
  • Concomitant ingestions? (AC may still be useful for other agents that may be present)
25
Q

What is NAC?

A

Thiol-containing agent which is deacetylated in the body to cysteine (precursor of glutathione)

26
Q

What is the MOA of NAC?

A
  • precursor of the synthesis of glutathione and sulfate (prevents depletion of these)
  • direct binding to NAPQI (GSH substitute)
  • modulation of cascade of inflammatory events
  • non-specific antioxidant effects and mediation of microvascular tone = improved organ function
27
Q

What is the US loading dose of NAC?

A

140mg/kg orally

28
Q

What is the US maintenance dose of NAC?

A

70mg/kg every 4 hours for additional 17 doses

29
Q

What is the protocol for NAC in Canada and UK ?

A

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

30
Q

Describe NAC

A
  • foul smelling
  • foul tasting
  • irritating to stomach
31
Q

What should we administer NAC with?

A

orange/grapefruit juice or soda and antiemetics

32
Q

What can rapid IV administration of NAC cause?

A

flushing, hypotension, bronchoconstriction (anaphylactoid reactions)

33
Q

NAC is most effective if administered within _____ hours of APAP ingestion

A

8-10

34
Q

Is NAC safe in pregnancy?

A

appears to be safe

35
Q

What defines chronic acetaminophen toxicity in adults?

A

daily consumption of doses more than 4-6 grams/day by alcoholic patients

36
Q

What defines chronic acetaminophen toxicity in children?

A

60-150 mg/kg/day for 2-8 days

37
Q

When do we use NAC in chronic toxicity?

A

if liver enzymes are elevated or high-risk patients

38
Q

What are risk factors for acetaminophen toxicity?

A
  • alcoholism
  • chronic treatment with anticonvulsants or isoniazid
  • fasting and malnutrition

*alcohol + acetaminophen + malnutrition + toxicity

Year 4 - Toxicology (24 decks)

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