Paracetamol is a COX inhibitor (like aspirin and NSAIDs)

What is COX?

Cyclo-oxygenase (COX) is an enzyme that produces:

• Prostaglandins - pro-inflammatory, hyperalgesic, gastroprotective and renoprotective.
• Thromboxane A2 - promotes platelet aggregation

COX-1 maintains normal functions:

• Protecting the gastric mucosa
• Maintaining renal perfusion
• Promoting platelet aggregation

COX-2 is upregulated in endothelial damage, causing:

• Pain
• Inflammation (Capillary vasodilatation and Increased capillary permeability)

BUT, paracetamol is a bit different to NSAIDs...

• Paracetamol is a really weak inhibitor of the COX-1 and -2 enzymes. And so, paracetamol is a weak anti-inflammatory, (unlike the Non-Steroidal ANTI-INFLAMMATORY Drugs) and has no anti-platelet effect (unlike aspirin).
• BUT paracetamol is a pretty good analgesic. The level to which paracetamol inhibits COX-2 (which is not very much) is disproportionate to the level of analgesia it produces- so, maybe paracetamol is providing its analgesic effects in a different way to other COX inhibitors?...
• The existence of a 3rd isoform of cyclo-oxygensase - COX-3 - has been proposed as the site of action of paracetamol and it is thought that COX-3 exhibits its effects on the central nervous system rather than in peripheral nerves like COX-2. This is also where paracetamol is thought to exhibit its anti-pyretic effect.

Analgesic

Paracetamol is pretty much used as the 1st line analgesic for any mild-moderate pain. It is widely available OTC in the community and its role in the acute setting is sometimes under-appreciated as it can be an effective analgesic when given intravenously.

The list of specific indications for paracetamol is almost inexhaustive but some common uses include:

Osteoarthritis

1st line analgesia: paracetamol + topical NSAIDs.

Sore throat (pharyngitis, tonsillitis, laryngitis)

1st line analgesia: Paracetamol/ibuprofen.

Migraine

1st line analgesia: oral triptan + paracetamol/NSAID

Anti-pyretic

Paracetamol is recommended as an anti-pyretic in those with a temperature >38.4C.

• Paracetamol is thought to be very safe and has very few side-effects (that we know of!) - this is why it is preferred to NSAIDs and aspirin.

Liver failure in overdose

Paracetamol is conjugated in 2 ways:

• Normal pathway (90%) - produces glucuronide and sulphate
• Alternative pathway (8%) - uses cP450 to produce N-acetyl-p-benzoquinone imine (NAPQI) which is toxic
• In low doses NAPQI is inactivated by glutathione stores in the liver, if glutathione stores are <30% normal then NAPQI begins to cause necrosis of hepatocytes and renal tubular cells

What dose can cause liver failure?

• <150mg/kg - unlikely
• <250mg/kg - likely
• >12g total ingestion (24 x 500mg tablets) - potentially fatal

Risk factors:

• Enzyme inducers: rifampicin, phenytoin, carbamazepine, ETOH, St John's wart
• Malnourishment (causes depletion of glutathione stores): e.g. anorexia, bullimia, CF, Hepatitis C, HIV