K4i / 14A05: Paracetamol

14A05: Exam Report

Describe the pharmacological effects of paracetamol. (40% of marks) Outline its toxic effects and their management. (60% of marks)

63% of candidates passed this question.

This   question   was   generally   well   answered   with   narrow   variance; very   few   candidates  discussed   factors   predisposing   to   hepato−toxicity   or   renal   toxicity. Discussion   of  pharmacokinetics  only  gained  marks  when  relevant  to  toxicity.    

K4i / 14A05: Describe the pharmacological effects of paracetamol (40 marks). Outline its toxic effects and their management (60 marks)

Paracetamol

Chemical

An acetanilide derivative

Use

  1. Analgesia
  2. Antipyretic

Presentation

  • Tablets
  • Syrup
  • Rectal suppositories
  • IV →   glass vial & argon, drug is unstable in O2 rich environment

Dose

1g QID

Route

PO/PR/IV

Onset

  • Peak [ ] 1hr 30mcg/mL
  • Therapeutic range 10 – 20mcg/mL
  • In 4hrs [   ] <10mcg/mL

MoA (mechanism)

Antipyretic

  • Inhibits central PG synthesis
  • Especially PGE in anterior hypothalamus

Analgesia

  • Inhibits peripheral Subs P actions
  • Potent central PG synthesis
  • Peripherally blocks impulse generation with BK sensitive chemoreceptors

PD

CNS

  • Analgesia
  • Antipyretic

PK

A

High lipid solubility

Rapid absorption

OBA 60 – 90%

More PR (OBA)

D

pKa 9.5 (weak acid)

<1% PPB

Highly UNIONISED at pH 7.4

Lipid soluble

Penetrates BBB +++

VD 1L/kg

M

HER 0.3

80% to glucuronide & sulphate

10% to NAPGI via CYP450 which is then conjugated with glutathione

E

<5% unchanged in urine

Metabolites actively secreted into renal tubules

t ½ B 2 – 4hrs

Adverse Effects

PARACETAMOL TOXICITY

Toxicity = the degree to which something is poisonous

·         Paracetamol therapeutic range = 10 – 20mcg/mL

·         Toxicity occurs if >10g ingested/24hrs

Metabolised by 2 pathways

1.      90% metabolised to glucuronide & sulphate

2.      10% metabolised by CYP450 to NAPQI →   then conjugated to glutathione

Mechanism of toxicity

·         ↑NAPQI levels

·         Forms covalent bonds with sulphadryl groups on hepatocytes →   cell death →   centrilobular necrosis

4 mechanisms of liver damage

1.      Excess paracetamol

2.      Excess CYP261 activity →   inducers (phenytoin; rifampicin)

3.      ↓ capacity to metabolise to glucuronide/sulphate

4.      ↓ glutathione stores

When NAPQI reacts with hepatocytes = IRREVERSIBLE INJURY

Nephrotoxicity

·         Metabolite p-aminophenol accumulates in renal papillae

·         Causes necrosis because binds covalently to sulphydryl groups & depletes glutathione

Cf. NSAID nephrotoxicity →   persistent PG synthesis inhibition →   medullary ischaemia

Toxicity S+S

·         N&V

·         Epigastric pain

·         Sweating

·         Acute haemolytic AN

·         Shock

·         Delayed hyperglycaemia

·         Hepatic failure in 48hrs

·         Fulminant hepatic failure 3 – 7 days

TREATMENT

·         Activated charcoal in 4hrs

·         ABC, IV glucose

·         NAC →   metabolized to glutathione which can conjugate with NAPQI

·         Treatment based on normogran (Rumack-Mathew)

Paracetamol