Paracetamol

Reviewed and revised 11 November 2016

CLASS

  • simple analgesic and antipyretic – not an NSAID as it lacks significant anti-inflammatory 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-pyretic

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
  • interstitial 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

LITFL

Journal articles

  • Jefferies S, Saxena M, Young P. Paracetamol in critical illness: a review. Critical care and Resuscitation. 14(1):74-80. 2012. [pubmed]
  • 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)

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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