Acetaminophen toxicity

Pathophysiology

• APAP (n-acetyl-p-aminophenol) liver metabolized by oxidation and/or conjugation
  • toxic metabolites, including N-acetyl-benzoquinonimine (NAPQI), metabolized via all 3
  • conjugation with glucuronide (40-60%) or sulfate (20-40%)
  • oxidation via CYP450 2E1 (<10%) and then conjugated
• In excessive amounts, glutathione depleted --> CYP450 pathway overwhelmed --> NAPQI accum = liver injury
• N-acetylcysteine (NAC) increases availability of glutathione thus prevents accumulation of NAPQI
• Additional effects of NAC: Antioxidant effects, microcirculatory changes (improved tissue oxygenation)
• Activated charcoal: Adsorbs (and prevents absorption of) acetaminophen
• However, also adsorbs (and prevents absorption of) N-acetylcysteine

Risk Factors for Toxicity

• Hepatic disease, alcoholics, geriatric: chronic toxicity
• Toxicity enhanced with inducers of CYP450 (alcoholics, drugs), poor nutrition (lower glutathione stores)

Kinetics

• t1/2: 4 hrs in OD, otherwise 1-3 hrs
• Usual maximum daily recommended dose: 2.4 - 4.0 g/day
• Thx dose: Peds - 15mg/kg/dose Q4-6; Adults - 325mg-1000mg Q4-6
• Toxic dose 140mg/kg; 10g or 200mg/kg; 4g or 100mg/kg in high risk pt

Metabolism:

• CYP450 dependent (in absence of sufficient glutathione)
• Children with less of cytochrome; less likely to suffer effects of toxicity
• Pediatric to Adult "metabolism" typically occurs between 6 to 9 years old

Symptoms

-Phase 1 (0-24 hrs): asymptomatic, N/V, abd. tenderness, diaphoresis

-Phase 2 (24-72 hrs): asymptomatic, LFT's & coagulation tests, Cr may begin to incr.

-Phase 3 (72-124 hrs): PEAK hepatotoxicity, hepatic necrosis, jaundice, encephalopathy, renal failure, death, pancreatitis (hyperamylasemia)

--Seen in 18% of overdoses

-Phase 4 (5-14 d): recovery

Work UP

Laboratory testing

-Lytes, BUN/Cr, glucose: metabolic acidos seen w/ extremely large (> 75 g, > 10 g peds) ingestion, renal function

-LFT's: AST usually incr. first; may rise over 10,000

-Monitor qd x3 with bilirubin

-Coagulation studies: indicator of liver function; monitor qD x3

-Acetaminophen level: 4 hours post ingestion and repeat in 4 hours

-Estimated ingestion >150 mg/kg and 8 hr post ingestion may start NAC while awaiting levels

-Rumack-Matthews nomogram guide for Tx in acute overdose; do not use for chronic ingestions or late ingestions

Toxic levels

-4 hr level >150 mcg/mL [993 umol/L]

-6 hr >110 mcg/mL [728 umol/L]

-8 hr >75 mcg/mL [496.5 umol/L]

-24 hr >4.5 mcg/mL [29.8 umol/L]

Acetaminophen half-life > 4 hr also may indicate toxicity

Extended release preparations (Tylenol7 "Extended Relief")

-Bi-layer caplet; each layer contains 325 mg acetaminophen

-One layer "immediate release," second layer "extended release" (up to 8 hrs; 95% released by 5 hrs)

-Peak blood levels with therapeutic doses @ 1-2 hrs; may be longer after overdose

-Requires serial levels (x2-3) as will drop and can be misleading

-Cannot use nomogram

-If suspicious, treat with NAC

-Does not qualify for new shorter course 48 hr NAC therapy

Treatment

1. Call poison control
2. ABCs, IV, O2, monitor
   • Decrease absorption
   • Do not induce emesis
3. Gastric lavage if < 1 hr post-ingestion
4. Activated charcoal if < 3 hr post-ingestion or if other coingestants
   • Does not interfere with NAC administration
5. Antidote: N-acetylcysteine (NAC or Mucomyst)
   • Obtain acetaminophen level at least 4 hrs after ingestion (if uncertain time, obtain level immediately and then 4hrs later; determine 1/2 life)
   • Wait for level before initiating therapy if level will return within 8 hrs post-ingestion
   • Plot on Rumack-Matthew nomogram; if acetaminophen level in non-toxic range, NAC not indicated
   • If level will not return within 8 hrs post-ingestion, give first dose of NAC empirically with suspected toxic ingestion; discontinue therapy if level non-toxic

If toxic:

1. NAC
2. PO:
   • 140 mg/kg PO load
   • 70 mg/kg PO q4hr x17 doses additional; dilute to 5% soln
3. IV (Acetadote)
   • Loading dose 150 mg/kg in 200 mL D5W over 60 min
   • Second (maintenance) dose 50 mg/kg in 500 mL D5W over 4 hrs
   • Third dose 100 mg/kg in 1000 mL D5W over 16 hrs
     • Virtually 100% effective if given < 8 hr post-ingestion; less effective if 16-24 hr post-ingestion
     • May still be useful > 24 hr post-ingestion; even with fulminant hepatic failure
     • Do not stop when acetaminophen concentrations fall to 0: free radicals are still causing hepatic damage
     • In pts who develop hepatic injury, NAC tx should be continued until liver function improves (follow LFT's)

5. May require strong anti-emetic (ondansetron 0.15 mg/kg IV, metoclopramide 20-40mg IV) or NGT if severe vomiting

6. Increase elimination

-Charcoal hemoperfusion

--Also effective in removing acetaminophen

--Not useful in usual clinical circumstances

--Indicated when pt. has fulminant hepatic encephalopathy with significant levels of acetaminophen present

7. Follow acetaminophen levels q4h, LFT, Coags

8. Evaluate potential need for liver transplant: pH<7.25, Cr >2.5, INR >4.5

Disposition

• Psych hold
• Admit
  • Pre-school child with ingestions > 200 mg/kg
  • Older child, adult w/ingestion >150 mg/kg or a total dose of 7.5 g
  • Liver function abnormalities
  • Delayed presentation or requirement for NAC therapy
• Discharge
  • Asymptomatic pts. w/o need of NAC therapy