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