Management of APAP Toxicity Flashcards


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1

Absorption pharmacokinetics of APAP

  • Tmax = ~30-60 min
  • ER = 4 h
  • F = 75% (bioavailability)

2

Distribution pharmacokinetics of APAP

  • Vd = 0.9-1.0 L/kg
  • pB = 10-30% (protein binding)
  • Therapeutic level = 10-30 mcg/mL

3

Metabolism pharmacokinetics of APAP

  • Primarily hepatic via conjugation
    • Glucuronidation and sulfation
  • Minimal renal excretion
  • Minimal formation of NAPQI

4

Elimination pharmacokinetics of APAP

  • 1st order
  • T1/2 = 2-4 hours

5

Absorption toxicokinetics of APAP

  • F = 75%
  • Tmax = ~4 h
  • ER = >4 h

6

Distribution toxicokinetics of APAP

  • Vd = 0.9-1.0 L/kg
  • pB = 10-30%
  • Toxic level = 150 mcg/mL at 4 hours

7

Metabolism toxicokinetics of APAP

  • Decreased conjugation
  • Minimal renal excretion
  • Increased formation of NAPQI

8

Elimination of toxicokinetics of APAP

  • 1st order
  • T1/2 = 2-4 hours, predictive of more severe
    outcomes if increased

9

In APAP overdoses, overtime

NAPQI keeps making and it sits around in the liver and causes damage

(does not get metabolized)

10

Accumulation of the toxic metabolite of acetaminophen is due to saturation of which metabolic pathway?

Glucuronidation and sulfation

11

MOA of acetaminophen

inhibits PGH2 formation via inhibition of COX via heme reduction on the peroxidase portion

(occurs more in CNS)

12

Pathophysiology of APAP overdose

increased production of NAPQI in overdose overwhelms GSH supply--> NAPQI generation causes GSH turnover--> NAPQI arylates proteins in hepatocytes--> forms protein adducts--> triggers hepatic cell death

13

What happens in stage I (0-24 hours) of APAP toxicity

N/V or abdominal pain, may be asymptomatic

14

What happens in stage II (24 hours- 36 hours) of APAP toxicity

worsening of GI symptoms, developing transaminitis (increase in ALT/AST), APAP-induced hepatotoxicity=AST or ALT >1,000

15

What happens in stage III (72 hours -96 hours) of APAP toxicity

fulminant hepatic failure, death, cerebral edema, sepsis, hemorrhage (rare), acute respiratory distress syndrome

16

What happens in stage IV (~7 days) of APAP toxicity

recovery, normalization of labs

17

What 3 things happen to the liver when APAP toxicity happens

transaminitis, hyperbilirubinemia, coagulopathy

18

What 3 things happen to the GI when APAP toxicity happens

nausea, vomiting, abdominal pain

19

What happens to the kidneys when APAP toxicity happens

AKI

20

What happens to the CNS when APAP toxicity happens

confusion, altered mental status

21

What is the primary mechanism of toxicity of acetaminophen

centralobar necrosis due to NAPQI accumulation leading to acute liver failure

22

General management of a poisoned patient

ABCs->discontinue exposure->external decontamination-> internal (GI) decontamination-> labs and monitoring parameters->therapeutic interventions

23

What can be used for internal decontamination

activated charcoal

24

Whats labs should be monitored after APAP toxicity

vitals, baseline-CMP, PT/INR, 4-hour post ingestion (APAP) if acute, coingestants (ASA and ETOH)

25

What should you consider after 4 hour post-ingestion of APAP

consider repeat level at 6-8 hours if co-formulated with anticholinergic/opioid or ER formulation

26

What can you use to see predict APAP-induced hepatotoxicity

rumack-matthew nomogram

27

Antidote of APAP

N-acetylcysteine (NAC)

28

MOA of N-acetylcysteine

detoxification of NAPQI directly, free radical scavenger, increases oxygen delivery and ATP production, GSH precursor to increase GSH production, substrate for sulfation, modulates inflammatory cascade cause by NAPQI

29

When to give NAC

acute: APAP is above the treatment line, unknown time of ingestion and detectable APAP or abnormal LFTS

chronic: detectable APAP, transaminitis, clinical judgement

30

Standard dosing regimen over 72 hours for Mucomyst

loading dose: 140 mg/kg PO x 1 dose

maintenance dose: 70 mg/kg PO every 4 hours x 17 doses

(not really used)

31

Standard dosing regimen over 21 hours for Acetadote (3-bag method)

loading dose: 150 mg/kg IV over 1 hour

1st maintenance dose: 50 mg/kg IV over 4 hours

2nd maintenance dose: 100 mg/kg IV over 16 hours

32

NAC adverse drug effects when given IV

anaphylactoid reaction (rate related, occurs within 6 hours), transient INR elevation

33

What to recommend when anaphylactoid reaction occurs

pause infusion, administer diphenhydramine, restart infusion at lower rate

34

NAC adverse drug effects when given PO

N/V

35

What to recommend when nausea and vomiting occurs

smell is noxious due to high sulfur content, prepare outside of room, administer in cup with lid and straw, dilute with cola or orange juice, chill with ice, administer antiemetics

36

What labs must be drawn 2 hours prior to the end of the 2nd maintenance dose or prior to the end of any subsequent 16 hour dose

LFTs, PT/INR, APAP

37

What must be met, otherwise the 16 hour bag is repeated

  • AST/ALT less than 100 and down trending
  • INR less than 1.5
  • APAP undetectable

38

What can be used for methanol or ethylene glycol ingestions and also for APAP overdoses

Fomepizole

39

MOA of Fomepizole

  • CYP2E1 inhibition decreasing NAPQI formation
  • inhibition of cell death pathways- prevents MAP kinase cascade from activating c-Jun N-terminal (JNK) via phosphorylation