Paracetamol

History

In 1852 Anilide was acetylated to Acetanilide. The therapeutic effect of Acetanilide was discovered by accident when in 1886 it was delivered in error instead of Naphthalene. The physicians discovered its anti-pyretic effects. Later other Analine derivatives were synthesised with Phenacetin introduced in 1888. Mehring reported investigations with paracetamol in 1892, as a para-aminophenol derivative. Most of the early products were used as antipyretics rather than analgesics, at a time when opiates predominated. The analgesic effect was recognised in the last 1940s. Winthrop introduced "Panadol" in 1956. It was slowly accepted by the medical profession, and appeared in the BNF in 1963. The product has steadily replaced Aspirin products, primarily for musculoskeletal pain and headache.

Actions

It is primarily analgesic and anti-pyretic, but may be useful for PDA closure. It works in the central nervous system. It inhibits prostaglandin synthesis. It resembles the selective COX 2 inhibitors. It is generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes in the brain.

Pharmacodynamics

Which central effects are largely responsible for Paracetamol effects on pain continue to be uncertain. The most accepted theory is that it has positive effects on the serotonergic descending inhibitory pathways. There may also be involvement with the opioidergic, eicosanoid, and nitric oxide systems. IT has been recently suggested that paracetamol is a pro-drug of a fatty acide amide called N-arachidonoylphenolamine, which acts directly on vanilloid subtype 1 receptors and indirectly on cannabinoid type 1 receptors in the CND thermoregulatory and noniceptive pathways. It shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely it has little activity at substantial levels of arachidonic acid and peroxides, hence it's lack of an anti-inflammatory effect. The lack of such peripheral COX inhibition confers a safer side-effect profile.

Pharmacokinetics

It is rapidly and almost completely absorbed from the GI tract. The presence of food int4erferes with absorption. Rectal absorption is more variable. Oral and rectal administration can produce analgesia within 40 mins.