In ammopharmacology, Vol. 11, No. 4–6, pp.

401– 413 (2003)

Ó VSP 2003.
Also available online - www.vsppub.com

Mechanisms of action of paracetamol and related

analgesics

GARRY G. GRAHAM 1;2;¤ and KIERAN F. SCOTT 1

1 School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
2 Department of Clinical Pharmacology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia

Abstract—Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-
1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low
concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased
levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme
involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol
and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower  ux through
this pathway produces lesser levels of the hydroperoxide, PGG2 , than the pathway involving COX-1.
Apart from the lack of anti-in ammatory effect of paracetamol in rheumatoid arthritis, the clinical
effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2
inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but,
further work, particularly at low concentrations of arachidonic acid is required. We suggest that
paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct
class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs
(PSAADs).

Key words: Paracetamol; acetaminophen; salicylate; dipyrone; prostaglandin; COX-1; COX-2; COX-
3; peroxidase.

1. INTRODUCTION
Paracetamol and salicylate have analgesic and antipyretic effects which resemble
those of the NSAIDs. They are weakly anti-in ammatory at analgesic and
antipyretic doses and are stated widely to be weak inhibitors of prostaglandin (PG)
synthesis and therefore must have other mechanisms of action. This conclusion is
not supported by critical examination of the literature. Our analysis indicates that
these drugs have a strikingly similar pharmacological proŽ le and that they are potent

¤ To
whom correspondence should be addressed at the Department of Clinical Pharmacology. Tel.:
(61-2) 8382-2955; e-mail: ggraham@stvincents.com.au
402 G. G. Graham and K. F. Scott

inhibitors of PG synthesis in intact cells under some conditions. Furthermore, they

appear to have a common mechanism of action which differs from those of the
classical NSAIDs and may represent a distinct class of NSAID. The pyrazolones
may be members of this class but data are limited.
Paracetamol is, of course, a widely used analgesic and antipyretic agent. Sali-
cylate salts have been administered in the past as analgesics, antipyretics and anti-
in ammatory drugs, but the present clinical interest in salicylate is very largely
because it is an active metabolite of aspirin. Thus, the activity of aspirin is due
both to aspirin and its metabolite, salicylate. The pyrazolones, such as antipyrine
(phenazone), dipyrone and aminopyrine are little used although dipyrone is avail-
able in some countries. Dipyrone is not absorbed intact and its activity is very
largely due to its immediate metabolite, methylaminoantipyrine.

2. THERAPEUTIC CONCENTRATIONS OF PARACETAMOL AND

SALICYLATE

For paracetamol, the therapeutic concentrations are of the order of 10 to 100 ¹M.
This approximate range is based Ž rstly on the plasma concentration of paraceta-
mol (22 ¹M) which is associated with 50% of maximal analgesic effect in children
undergoing tonsillectomy (Anderson et al., 1999). Secondly, peak plasma concen-
trations after oral dosage of rapidly absorbed formulations are about 100 to 200
¹M although the peak tissue concentrations, for example in cerebrospinal  uid, are
about 50% of the peak values (Bannwarth et al., 1992). Paracetamol is not bound
to plasma proteins and such binding does not have to be considered.
The therapeutic plasma concentrations for the anti-in ammatory effect of sali-
cylate are commonly quoted as 1.1 to 2.2 ¹M. The binding to plasma proteins is
saturable and the corresponding unbound concentrations are approximately 140 to
500 ¹M (Shen et al., 1991). Analgesia is, however, produced by lower plasma con-
centrations of salicylate. For example, a 1-g dose of sodium salicylate is analgesic
and produces peak plasma concentrations of unbound salicylate of about 50 ¹M
(Graham et al., 1976). Even lower concentrations may lead to analgesia.

3. RELEVANT ENZYMOLOGY OF PG SYNTHESIS

The dual actions of cyclooxygenase-1 (COX-1) and COX-2 are important consider-
ations in any discussion of the effects of paracetamol and related drugs. Both COX-
1 and COX-2 catalyze the production of PGG2 from the most common substrate,
arachidonic acid, which is liberated from phospholipid by the activity of cPLA2 -®.
This reaction is catalyzed by the cyclooxygenase activity of the enzymes. The per-
oxidase function of the enzymes then converts PGG2 to PGH2 which is the branch
point for the formation of the various prostanoids such as PGE2, prostacyclin and
thromboxane A2 . Thus, speciŽ c enzymes catalyse the formation of these various