- 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)
Paracetamol
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
Uses
- Analgesic
- Anti-pyretic
Mechanisms of action
- The mechanism(s) of action of paracetamol are not fully elucidated
- It is generally thought to be a COX-2 (predominantly, but also some COX-1) enzyme modulator leading to reduced prostaglandin synthesis
- AM404, formed in the CNS by metabolism of the paracetamol metabolite 4-aminophenol, is felt to cause analgesia by:
- Weak agonism at CB1 and CB2 endocannabinoid receptors, and inhibition of endocannabinoid transport
- TRPV1 activation, blocking impulses associated with bradykinin-sensitive chemoreceptors responsible for transmission of nociceptive stimuli
- Other putative mechanisms include:
- 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
- The previous theory that it selectively inhibited central COX-3, reducing central prostaglandin production, is now felt to be incorrect owing to a lack of COX-3 gene expression in humans
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:
- Conjugation (90%) to:
- Glucuronide conjugates (50%)
- Sulphate (35%) conjugates
- Cysteine conjugates
- 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