ANALGESICS - Acetaminophen

Acetaminophen

Drug Class: antipyretics, analgesics
Drug: acetaminophen [Tylenol], acetaminophen with codeine [Tylenol #1, #2, #3, #4]

Mechanism of Action & Indications

• Inhibits synthesis of prostaglandins in the central nervous system and peripherally, blocking pain impulse generation.
• Antipyretic action by inhibition of hypothalamic heat-regulating center.

Common Dosage

• Acetaminophen 325-650mg PO q4-6h, maximum dose 4g/day
• Acetaminophen extra-strength 500-1000mg PO q4-6h, maximum dose 4g/day

Adverse Effects

• Generally a well-tolerated medication with minimal side effects if used appropriately.
• The toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is normally inactivated by glutathione (sulfhydryl donor). In the setting of large amount of this toxic
  metabolite (≥4g daily), glutathione conjugation becomes insufficient. NAPQI then
  binds covalently with cellular macromolecules, causing potential hepatic cell
  necrosis and acute renal failure. N-acetylcysteine, the antidote, regenerates hepatic
  glutathione stores.
• Acute overdose with a single dose of >10g (twenty 500mg tablets) can produce liver injury. Fulminant hepatic failure is associated with ingestion >25g.
• Chronic liver damage has been reported with long term use in adults of 5-8g/day for several weeks, or 3-4 g/day for one year.

Practical Tips

• For patients with liver disease/cirrhosis or malnutrition, limited low-dose therapy is usually well tolerated. However, hepatotoxicity at dosages <4 g/day have been reported. Avoid chronic use if hepatic impairment or heavy alcohol use.
• Caution in patients with alcoholic liver disease (≥3 drinks/day), as this may increase the risk of hepatotoxicity.
• Metabolized by the liver and excreted in urine. For patients with renal failure, consider dosing interval adjustment as metabolites may accumulate (q6h if creatinine clearance 10-50ml/min, and q8h if creatinine clearance <10ml/min).
• Unlike ASA or NSAIDs, acetaminophen does NOT have anti-inflammatory effect.
• Acetaminophen is combined with codeine in Tylenol #1 (300mg/8mg) and Tylenol #2 (300mg/15mg), Tylenol #3 (300mg/30mg) and Tylenol #4 (300mg/60mg) for better pain control. However, in patients with severe pain, the amount of codeine is limited by the maximum dose of acetaminophen. Consider replacing Tylenol #1- 4 with acetaminophen plus an opioid (e.g. morphine, codeine) as separate prescriptions.
• Caution in patients with febrile neutropenia or severe infections as acetaminophen may mask the fever, leading to delayed treatment of life-threatening infections. If symptomatic relief needed, consider a single dose at a time after fever documented and appropriate actions taken (blood cultures, antibiotics). 
• Treatment of acetaminophen overdose with N-acetylcysteine: 150mg/kg (~60ml) in 200cc D5W over 1hr, then 50mg/kg (~20ml) in 500cc D5W over 4hr, then 100mg/kg (~40ml) in 1L D5W over 16hr. Alternatively, N-acetylcysteine 140mg/kg PO/NG, followed by 70mg/kg q4h for 17 doses.