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

DOSE

INDICATIONS

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

Lifeinthefastlane.com

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)