paracetamol (acetaminophen)

introduction:

rapidly absorbed from GIT - peak concentration 60-120mins if tablet or capsule form ingested
Vd 1.0-2.0L/kg
half life 1-3hrs but may increase to 17hrs in liver disease
metabolised by liver:
- 52% by sulphation
- 42% by glucuronidation
- 2% excreted unchanged in urine
- 4% biotransformed by C-P450 MFO system
- but in overdose when glutathione stores are depleted, N-acetyl-p-benzoquinoneimine (NAPQI) accumulates and causes hepatocellular necrosis

antipyretic analgesic
its analgesic actions appear to require CB1 receptors ¹⁾
a secondary metabolite N-arachidonoylaminophenol (AM404) of paracetamol has multiple effects on cannabinoid signaling including blockade of anandamide uptake; inhibition of fatty acid amide hydrolase (FAAH), an enzyme that metabolizes the eCB arachidonoylethanolamine (anandamide); and indirect activation of TRPV110 and/or cannabinoid receptors.
inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol (2-AG) which makes one of the endogenous cannabinoids resulting in reduced CB1 activation which may have a role in nociception ²⁾
inhibits pain impulses peripherally
inhibits brain prostaglandin synthetase
may also:
- decrease empathy ³⁾
- decrease feelings of joy
- decrease anxiety and existential dread
- have potential fetal effects when taken in pregnancy - unproven - further research needed

adults:
- 500-1000mg 4-6hr prn (max. 4g per day - ie. 2 x 500mg tablets qid)
paed:
- 15mg/kg/dose 4-6hr max. 90mg/kg/24hr
- a single evening stat dose up to 30mg/kg can be used with care as long as total daily max. dose of 90mg/kg/d is not exceeded

paracetamol is generally a very safe drug with few adverse effects and is well tolerated.
HOWEVER, in excessive dosing(s), fatal hepatotoxicity may occur
see paracetamol overdose
even normal doses may cause fatal liver failure if prolonged in susceptible patients (eg. malnourished or those with liver disease)
- for example, see:
  - here (MJA 2007) for a fatal case where a 45yr old lady was ordered 1g paracetamol qid strictly for 8 days whilst nil by mouth for an abdominal surgical condition.
  - https://www.abc.net.au/news/2024-09-18/paracetamol-overdose-death-canberra-hospital-liver-failure/104362348 - ACT coroner finds 73yr old lady died from excessive IV paracetamol doses given to her in hospital over 5 days in 2021 as her weight of 39kg was not taken into account

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