Document Detail


Paracetamol (Acetaminophen): mechanisms of action.
MedLine Citation:
PMID:  18811827     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H(2) synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH(2). The two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG(2) is dependent on a tyrosine-385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe(3+) at the POX site is essential for conversion of tyrosine-385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide-generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG(2). Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti-inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p-aminophenol). p-Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.
Authors:
Brian J Anderson
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Paediatric anaesthesia     Volume:  18     ISSN:  1460-9592     ISO Abbreviation:  Paediatr Anaesth     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-24     Completed Date:  2009-01-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9206575     Medline TA:  Paediatr Anaesth     Country:  France    
Other Details:
Languages:  eng     Pagination:  915-21     Citation Subset:  IM    
Affiliation:
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. briana@adhb.govt.nz
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MeSH Terms
Descriptor/Qualifier:
Acetaminophen / pharmacology*
Analgesics, Non-Narcotic / pharmacology*
Arachidonic Acid / metabolism*
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / metabolism
Cyclooxygenase Inhibitors / pharmacology
Humans
Nitric Oxide / metabolism
Nociceptors / drug effects*,  metabolism
Peroxidase / drug effects,  metabolism
Prostaglandin H2 / metabolism
Prostaglandin-Endoperoxide Synthases / metabolism
Receptors, Cannabinoid / metabolism
Receptors, Prostaglandin / metabolism
Chemical
Reg. No./Substance:
0/Analgesics, Non-Narcotic; 0/Cyclooxygenase Inhibitors; 0/Receptors, Cannabinoid; 0/Receptors, Prostaglandin; 10102-43-9/Nitric Oxide; 103-90-2/Acetaminophen; 42935-17-1/Prostaglandin H2; 506-32-1/Arachidonic Acid; EC 1.11.1.7/Peroxidase; EC 1.14.99.1/Cyclooxygenase 1; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 1.14.99.1/cyclooxygenase-3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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