Paracetamol is used worldwide for its
analgesic and
antipyretic actions. It has a spectrum of action similar to that of
NSAIDs and resembles particularly the COX-2 selective inhibitors.
Paracetamol is, on average, a weaker
analgesic than
NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to
NSAIDs, the mode of action of
paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the
peroxidase function of these
isoenzymes. This results in inhibition of
phenoxyl radical formation from a critical
tyrosine residue essential for the
cyclooxygenase activity of COX-1 and COX-2 and
prostaglandin (PG) synthesis.
Paracetamol 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. The result is that
paracetamol does not suppress the severe
inflammation of
rheumatoid arthritis and acute
gout but does inhibit the lesser
inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals.
Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of
paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective
NSAIDs and selective
COX-2 inhibitors,
paracetamol inhibits other
peroxidase enzymes including
myeloperoxidase. Inhibition of
myeloperoxidase involves
paracetamol oxidation and concomitant decreased formation of halogenating
oxidants (e.g.
hypochlorous acid,
hypobromous acid) that may be associated with multiple inflammatory pathologies including
atherosclerosis and
rheumatic diseases.
Paracetamol may, therefore, slow the development of these diseases.
Paracetamol,
NSAIDs and selective
COX-2 inhibitors all have central and peripheral effects. As is the case with the
NSAIDs, including the selective
COX-2 inhibitors, the
analgesic effects of
paracetamol are reduced by inhibitors of many endogenous
neurotransmitter systems including serotonergic,
opioid and
cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of
paracetamol. Much of the toxicity may result from overuse of combinations of
paracetamol with
opioids which are widely used, particularly in USA.