Paracetamol

Reviewed and revised 11 November 2016

CLASS

• simple analgesic and antipyretic – not an NSAID as it lacks significant antinflammatory effects
• acetaminophen

MECHANISM OF ACTION

• Tissue- specific inhibitory effect on COX via a reduction reaction on the COX enzyme in the presence of a low peroxide environment
• CNS effects of paracetamol
  • selective inhibition of cyclo-oxygenase (COX) and decreased prostaglandin production
  • pro-drug of N-arachidonoylphenolamine (AM404)
    • acts directly on vanilloid subtype 1 receptors
    • acts indirectly on cannabinoid type 1 (CB1) receptors via decreased N-arachidonoylethanolamide uptake
    • affects thermoregulatory and nociceptive pathways
  • paracetamol may interact with opioid pathways
    • synergistic analgesic effect at spinal and supraspinal levels (mu, delta and kappa receptors)
• Peripheral effects
  • weak COX 1 & 2 inhibitor in peripheral tissues
  • blocks impulse generation within the bradykinin-sensitive chemoreceptors to decrease afferent nociceptive impulses
• poor anti-inflammatory and antiplatelet properties and better side-effect profile than NSAIDs due to peroxide sensitivity

PHARMACEUTICS

• IV, PO, PR
• modified release formulation is available (e.g. panadol osteo)

DOSE

• 20mg/kg load -then 15mg/kg Q4-6hrly
• maximum = 90mg/kg/day or 4g daily

INDICATIONS

1. analgesia
2. anti-pyresis

ADVERSE EFFECTS

• transient LFT changes
•  hepatotoxicity
  • acute overdose
  • repeated supratherapeutic ingestion
  • can occasionally occur with conventional paracetamol dosing (e.g. malnourished state, chronic excessive alcohol consumption)
• IV paracetamol associated with hypotension in the critically ill (affects up to 1/4 ICU patients) (Kelly et al, 2016)
• pyroglutamic acidosis (rare), usually in patients with sepsis and renal impairment treated with flucloxacillin
• allergy (rare)
• hemolytic anaemia and methaemoglobinaemia are very rare
• intersitial nephritis and papillary necrosis do not occur (as they did with the paracetamol precursor phenacetin)

PHARMACOKINETICS

• Absorption
  • rapid and complete from GI tract (gastric and small intestine) with peak blood concentrations at 30-60 min
  • slower and incomplete if given rectally
• Distribution
  • Vd 1L/kg (likely increased in critical illness)
  • poorly protein bound
  • non-ionised so penetrates BBB
• Metabolism
  • hepatic via saturatable glucuronidation and sulphation pathways
  • toxic metabolite NAPQI accumulates in overdose
• Elimination
  • t ½ = 2 h
  • relatively unaffected by renal function

EVIDENCE

• reduces temperature in fever by about 0.25C

References and links

Lifeinthefastlane.com

• CCC — Paracetamol in Critical Illness

Journal articles

• Jefferies S, Saxena M, Young P. Paracetamol in critical illness: a review. Critical care and Resuscitation. 14(1):74-80. 2012. [pubmed] [free fulltext]
• Kelly SJ, Moran JL, Williams PJ, et al. Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial. Anaesthesia. 71(10):1153-62. 2016. [pubmed]
• Young P, Saxena M, Bellomo R. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. The New England journal of medicine. 373(23):2215-24. 2015. [pubmed] (aka HEAT trial)