2019B14 Discuss the role of paracetamol in multi-modal analgesia (33%).
Explain paracetamol metabolism and the mechanism of toxicity (67%).
DO NOT discuss management of toxicity.

 

List:

·         Mechanism

·         Role

·         Metabolism

·         Toxicity

 

Mechanism:

·         ↑5HT activity -> ↑descending modulation (multiple receptor subtypes involved)

·         Endocannabinoid reuptake inhibition -> central analgesia, tranquility (paracetamol’s active CNS metabolite AM404)

·         Central COX inhibition: unclear effect and significance

·         Other: nitric oxide, opioid pathways

 

Role:

·         First step in the WHO analgesic ladder

·         Minimal side effects, low risk of toxicity

·         Reduces opioid use and opioid side effects

 

Metabolism:

·         Phase 2

o   Glucuronidation ~55%

o   Sulfation ~35%

·         Phase 1

o   CYP450 to NAPQI (N-acetyl P-benzquinonimine) ~10%

Toxicity:

·         With normal doses

o   NAPQI + glutathione -> cysteine conjugate, mercaptopuric acid conjugate

·         With high dose

o   Conjugation pathways saturated

o   ↑NAPQI production

o   Glutathione exhausted (earlier if malnourished)

o   ↑NAPQI accumulation

o   Damage to hepatic proteins

o   Centrilobular necrosis

o   Acute liver failure