The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings

Abstract

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.

Desalination and seawater quality at Green Point, Cape Town: A study on the effects of marine sewage outfalls (with corrigendum)

“…Unknown quantities of partially metabolised drugs which may be toxic are also released in faeces and urine. 21 Their molecular sizes in the nanometre (10 -9 ) and Angstrom range (10 -10 ) make it impossible for marine organisms to exclude them. It has been widely reported that these compounds are continuously released into the environment, [22][23][24] and bioaccumulate in wild-caught fish populations at concentrations of nanograms per gram.…”

Pharmacology: Inflammatory definitions

“…Interest in the Jaborandi plant by French physicians was piqued due to its use among Brazilian Indians to promote profuse sweating and salivation. 2 Because of its commercial value, this species was exploited without control and by the 1990s it was considered an endangered species in Brazil. 1 During the dry season collectors go into the forest and strip the leaves from branches by hand.…”

“…Excessive and frequent collection of leaves from the same plant does not allow full development of new leaves leading to high plant mortality and reduction in the size of new leaves. 2 Studies are being carried out to establish the biosynthetic route…”

“…Paracetamol (but also the other analgesic-antipyretic drugs to varying extent) share the pharmacodynamic properties of the traditional NSAIDs, but paracetamol's effects are shown in many in vitro experiments to be weaker. 2 These findings are referred to in textbooks with the statement that paracetamol is of little value as an 'anti-inflammatory' drug. It was therefore highly surprising that controlled clinical trials showed a paracetamol regimen compared with placebo 3 actually reduced objectively measured soft tissue swelling after third molar surgery on the third postoperative day much better (29%) than an ibuprofen regimen compared to placebo (11%).…”

Complicaciones digestivas y renales por indometacina e ibuprofeno en prematuros extremos con ductus arterioso permeable

“…If closure of the PAD is not achieved with one or two cycles of NSAID therapy, surgical closure is indicated 16 . More recently, paracetamol has been used, however clinical experience is still under development 17,18 .…”