Reviewed and revised 11 November 2016
CLASS
- simple analgesic and antipyretic –Â 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
- analgesia
- anti-pyresis
ADVERSE EFFECTS
- transient LFT changes
- Â 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)
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