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

1. t1/2: 4 hrs in OD, otherwise 1-3 hrs
2. Usual maximum daily recommended dose: 2.4 - 4.0 g/day
3. Thx dose:
   1. Peds - 15mg/kg/dose Q4-6
   2. Adults - 325mg-1000mg Q4-6
4. 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

1. Phase 1 (0-24 hrs): asymptomatic, N/V, abd. tenderness, diaphoresis
2. Phase 2 (24-72 hrs): asymptomatic, LFT's & coagulation tests, Cr may begin to incr.
3. Phase 3 (72-124 hrs): PEAK hepatotoxicity, hepatic necrosis, jaundice, encephalopathy, renal failure, death, pancreatitis (hyperamylasemia)
   1. Seen in 18% of overdoses
4. Phase 4 (5-14 d): recovery

Work UP

1. Lytes, BUN/Cr, glucose: metabolic acidos seen w/ extremely large (> 75 g, > 10 g peds) ingestion, renal function
2. LFT's: AST usually incr. first; may rise over 10,000
3. Monitor qd x3 with bilirubin
4. Coagulation studies: indicator of liver function; monitor qD x3
5. Acetaminophen level: 4 hours post ingestion and repeat in 4 hours
6. Estimated ingestion >150 mg/kg and 8 hr post ingestion may start NAC while awaiting levels
7. Rumack-Matthews nomogram guide for Tx in acute overdose; do not use for chronic ingestions or late ingestions

Toxic levels

1. 4 hr level >150 mcg/mL [993 umol/L]
2. 6 hr >110 mcg/mL [728 umol/L]
3. 8 hr >75 mcg/mL [496.5 umol/L]
4. 24 hr >4.5 mcg/mL [29.8 umol/L]

Acetaminophen half-life > 4 hr also may indicate toxicity

Extended Release (Tylenol7 "Extended Relief")

1. Bi-layer caplet; each layer contains 325 mg acetaminophen
2. One layer "immediate release," second layer "extended release" (up to 8 hrs; 95% released by 5 hrs)
3. Peak blood levels with therapeutic doses @ 1-2 hrs; may be longer after overdose
4. Requires serial levels (x2-3) as will drop and can be misleading
5. Cannot use nomogram
6. If suspicious, treat with NAC
7. Does not qualify for new shorter course 48 hr NAC therapy

Treatment

1. Call poison control
2. ABCs, IV, O2, monitor
3. Decrease absorption
   1. Do not induce emesis
   2. Gastric lavage if < 1 hr post-ingestion
4. Activated charcoal if < 3 hr post-ingestion or if other coingestants
   1. Does not interfere with NAC administration
5. Antidote: N-acetylcysteine (NAC or Mucomyst)
   1. Obtain acetaminophen level at least 4 hrs after ingestion (if uncertain time, obtain level immediately and then 4hrs later; determine 1/2 life)
   2. Wait for level before initiating therapy if level will return within 8 hrs post-ingestion
   3. Plot on Rumack-Matthew nomogram; if acetaminophen level in non-toxic range, NAC not indicated
   4. 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
   1. PO:
      1. 140 mg/kg PO load
      2. 70 mg/kg PO q4hr x17 doses additional; dilute to 5% soln
   2. IV (Acetadote)
      1. Loading dose 150 mg/kg in 200 mL D5W over 60 min
      2. Second (maintenance) dose 50 mg/kg in 500 mL D5W over 4 hrs
      3. Third dose 100 mg/kg in 1000 mL D5W over 16 hrs
   3. Virtually 100% effective if given < 8 hr post-ingestion; less effective if 16-24 hr post-ingestion
   4. May still be useful > 24 hr post-ingestion; even with fulminant hepatic failure
   5. Do not stop when acetaminophen concentrations fall to 0: free radicals are still causing hepatic damage
   6. In pts who develop hepatic injury, NAC tx should be continued until liver function improves (follow LFT's)
   7. May require strong anti-emetic (ondansetron 0.15 mg/kg IV, metoclopramide 20-40mg IV) or NGT if severe vomiting
2. Increase elimination
   1. Charcoal hemoperfusion
      1. Also effective in removing acetaminophen
      2. Not useful in usual clinical circumstances
      3. Indicated when pt. has fulminant hepatic encephalopathy with significant levels of acetaminophen present
3. Follow acetaminophen levels q4h, LFT, Coags
4. Evaluate potential need for liver transplant: pH<7.25, Cr >2.5, INR >4.5

Disposition

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

The "140" Rule

• Toxic dose is 140 mg/kg
• Give NAC if level is >140 mcg/mL four hours post-ingestion
• Initial loading dose of NAC is 140 mg/kg PO