Paracetamol

Question 1

Outline the theorized mechanisms of action of paracetamol

Answer 1

Mechanism for Analgesic effects of paracetamol:

• Poorly understood
• Mechanism 1: modifies cyclo-oyxgenase (COX) system WITHOUT affecting the inflammatory cascade -> inhibits peroxidase function of COX
• Mechanism 2: activates descending analgesic pathway of the CNS
  1) Relies on NT of descending analgesic pathway (i.e. serotonin, enkephalin, cannabinoid)
  2) Paracetamol effect reduced when these NT are inhibited
• Acts on all levels of pain stimulus

Question 2

Outline the uses for paracetamol use in dentistry

Answer 2

• First choice analgesic
• For mild to moderate pain
• Recommended dosage = 4g/day: Acts by depleting glutathione stores in liver
• Fast onset (<1hr)
• Short action (4-6 hours)

Question 3

Identify the maximum recommended dosage of paracetamol

Answer 3

• Maximum dosage: 4g per 24 hour

- Paracetamol has a narrow therapeutic index

Question 4

Describe pathology of over dosage of paracetamol

Answer 4

• Metabolized in liver and excreted in urine
• Toxic metabolites as intermediate product (NAPQI)
• Risk in patients with liver or kidney disease
• Removal of parcetamol:
  1) 90% metabolized by liver to inactive metabolites (conjugation) - sulphation: Conjugation with glucuronic acid, sulfuric acid, or cystine
  2) 5% eliminated unchanged by kidneys
  3) 5% metabolized by liver through toxic pathway to inactive metabolites (conjugation): cytochrome P450 enzyme converts Paracetamol to NAPQI (Toxic metabolite), NAPQI is inactivated by glutathione
• Overdose is accumulation of NAPQI
• Factors affecting toxicity:
  1) Increase Toxicity: CYP450 induction (Rifampicin, barbiturates and carbamazepine), Glutathione depletion (e.g. Liver disease)
  2) Decrease toxicity: CYP450 Inhibition, enhanced sulphation (of Paracetamol)
• NAPQI binds to liver macromolecules -> liver cell death
• Treatment: Minor over-dose: N-acetyl cysteine; Major overdose: liver transplantation