FRCA Notes

Paracetamol

  • Paracetamol is a para-amino-phenol acetanilide derivative
  • It is lumped together with the true NSAIDs owing to its anti-pyretic and analgesic properties
  • Tablets, either:
    • Alone (500mg/tablet)
    • In combination with weak opioids e.g. codeine as co-codamol
    • In combination with methionine (to prevent toxicity, but is rather costly)

  • Suppositories (125mg, 1g)
  • Suspension/elixir (120mg/5ml)
  • IV solution as a clear, colourless solution typically of 10mg/ml (500mg, 1g)

Uses

  • Analgesic
  • Anti-pyretic

Mechanisms of action

  • The mechanism(s) of action of paracetamol are not fully elucidated, but may include:
    • A COX-2 (peripheral) mechanism; doesn't cause clinically relevant antagonism but may modulate enzyme somewhat
    • Selective inhibition of central COX-3 and thus reduced central prostaglandin production, which may be responsible for its anti-pyretic effect (reduced hypothalamic PGE2)
    • Modulation of the endogenous cannabinoid system (mice lacking endocannabinoid receptors don't receive analgesic benefit from paracetamol)
    • Blocking impulses associated with bradykinin-sensitive chemoreceptors responsible for transmission of nociceptive stimuli e.g. TRPV1
    • An effect on the T-type Cav3.2 calcium channel, which modulates cellular excitability
    • Inhibition of NO synthesis
    • Enhancing activity of Kv7 potassium channels (by NAPQI)
    • Serotonergic effect


Absorption

  • pKa 9.5
  • Not absorbed in the stomach but well absorbed from the small bowel
    • Can therefore be used as a marker of gastric emptying
  • High oral bioavailability (80-90%)

Distribution

  • Only 10%-20% plasma protein bound (vs. other NSAIDs, which are highly protein bound)
  • VD 0.7 - 1L/kg (vs. other NSAIDs, which have lower volumes of distribution e.g. 0.1-0.2L/kg)
  • Peak plasma level 1hr after oral dosing

Metabolism

  • Metabolism is by hepatic CYP2E1 via:
    1. Conjugation (90%) to:
      • Glucuronide conjugates (50%)
      • Sulphate (35%) conjugates
      • Cysteine conjugates

    2. Oxidation (10%) to N-acetyl-p-amino-benzoquinone imine (NAPQI)
      • A highly toxic compound which is normally rapidly conjugated by hepatic glutathione and therefore harmless
      • Small amounts of NAPQI are produced with therapeutic dosing
      • This process also generates the free radical superoxide anion (O2-)

Excretion

  • Metabolites are actively excreted in the urine
  • A small fraction is excreted unchanged (up to 5%)
  • Elimination half life 2hrs

  • IV solution can cause hypotension and bradycardia if given rapidly
    • Paracetamol is an arteriodilator, possibly via the action of NAPQI on Kv7 potassium channels
  • Doesn't cause gastric irritation or other classical NSAID side-effects
  • Rash, ITP and nephropathy are described
  • Toxic in overdose