NAPQI, paracetamol metabolite, is severly hepatotoxic
N-acetyl-p-benzoquinonimine
generated by p450 enzymes
also causes paracetamol induced renal damage
generated by prostoglandin endoperoxide synthetase rather than p450
NAPQI is normally detoxified by interaction with glutathione (GSH) to form glutathione conjugate
mechanisms of NAPQI induced hepatic injury include:
glutathione depletion
direct oxidising and arylating effects
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Factors affecting hepatotoxicity I
dose ingested/absorbed
<75mg/kg = v unlikely
>150 mg/kg = possible
dep largely on pt size- e.g. 15 x 500mg tablet in a 50kg pt = 150mg/kg = possible
plasma paracetamol conc
use graph
>100mg/L 4 hrs post ingestion = possible
>50mg/L 8 hrs post
single vs staggered dose
OD over 60 mins=staggered dose
treat all staggered ODs w/ acetylcysteine
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Factors affecting hepatotoxicity II
time to antidote administration
glutathione precursors= IV acetylcysteine over 21 hours
bag 1: 150mg/kg in 200ml 5% glucose over 1 hour
bag 2 : 50mg/kg in 500ml 5% glucose over 4 hours
bag 3: 100mg/kg in 1000ml 5% glucose over 16 hours
acetylcysteine a/e: anaphylactoid features in 10-15%; flushing, urticuria, pruritus, bronchospasm, angio-oedema immdiately following admin- resolve by dicontinuing short time
histamine mediated thus give antihistamine if necessary
8 hour rule
treat w/in 8 hrs of ingestion- not at risk of sig lievr damage
thus wait for plasma conc following single OD provided it will be w/in 8 hrs of ingestion before deciding on Rx
late presenters= >8 hrs
if Rx >15 hrs post-OD, less reliable
NB hard to work out if liver damage possible if not sure of exact time later
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Clinical presentation
NB 24 hour rule: clinically significant hepatotoxicity is v unlikely if 24hrs after most recent P:
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