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