Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 13 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CHONDROPROTECTIVE AGENTS
● NSAIDs are used in the management of some immunological
diseases such as systemic lupus and rheumatoid
arthritis because of their anti-inflammatory
effects. However, research indicates that NSAIDs
may have a more direct effect in these diseases by
stimulating T-suppressor cells in their action against
T-helper cells and autoantibody-producing B cells.
● NSAIDs appear to have a role in the management
of endotoxic shock, as plasma concentrations of
prostaglandins, thromboxane and prostacyclin are
increased and are thought to contribute to the
decreased cardiac output, blood pressure, oxygen
tension and acidosis that occurs. However, if therapy
is to be effective it must be administered either prior
to or immediately after the onset of endotoxemia in
conjunction with other supportive therapy.
● NSAIDs are used as antipyretic agents in cattle and
other species. Because of this, they are used in cats
with high fevers and to a lesser extent in dogs.
Mechanism of action
The mechanism of action of NSAIDs includes inhibition
of several mediators of inflammation in the arachidonic
acid cascade (Fig. 13.1). Eicosanoids are formed from
Cyclooxygenase
pathway
COX-1
(physiologic)
Prostaglandins
thromboxane
Cell membrane phospholipids
Corticosteroids
NSAIDs
Phospholipase A 2
Arachidonic acid
COX-2
(inducible)
Prostaglandins
Coxib
NSAIDs
Lipoxygenase
pathway
LOX
(inducible)
Leukotrienes
LOX
NSAIDs
Fig. 13.1 Simplified illustration of the arachidonic acid
cascade. Corticosteroids act by inhibiting the activity of
phospholipase A 2 , thereby preventing the formation of
arachidonic acid. NSAIDs act by inhibiting components
of the cyclo-oxygenase and lipoxygenase pathways.
Within the cyclo-oxygenase pathway, activity may be
selective or nonselective for COX-1 and COX-2.
arachidonic acid by the action of COX and lipoxygenase
(LOX). COX activity leads to production of prostaglandins,
prostacyclins and thromboxanes, whereas
LOX activity leads to production of leukotrienes and
lipoxins.
It is currently understood that prostaglandin synthesis
is catalyzed by at least two forms of cyclo-oxygenase:
COX-1 and COX-2. COX is present in all cells except
mature blood cells. However, the distribution of COX
activity between and within tissues is very heterogenous.
COX-1 is constitutively expressed and enzymatically
active in a variety of tissues, including the stomach,
intestine, kidneys and platelets. COX-1 activity is primarily
physiological, including gastric mucosal protection,
renal blood flow and vascular hemostasis. In some
situations, COX-1 may have inflammatory activity, but
this is not its predominant function. COX-2 expression
is primarily induced by mediators such as serum growth
factors, cytokines and mitogens. COX-2 activity is primarily
associated with pathological processes (pain,
inflammation and fever). COX-2 has some physiological
activity related to maintenance of renal blood flow,
reproduction and cell signaling, but its activity is most
evident with inflammation.
Recently a third cyclo-oxygenase, COX-3, has been
reported. Although COX-3 is described as the product
of a splice variant of COX-1 and it may constitute the
centrally mediated mechanism of action for paracetamol
(acetaminophen), its exact role remains unclear. There
is evidence that additional COX variants will be delineated
in the future.
The other major products of arachidonic acid metabolism
are the leukotriene series, the production of which
is mediated by the enzyme LOX, found in lungs, platelets
and white blood cells. It has been hypothesized that
NSAIDs are less efficacious as anti-inflammatory agents
than glucocorticosteroids because precursor mediators
of inflammation are free to enter the lipoxygenase
pathway and still produce inflammation. Although it is
claimed that some NSAIDs, such as ketoprofen, also
inhibit lipoxygenase in vitro, this effect tends to be
species and tissue dependent and has not been demonstrated
with clinical dose rates in vivo. Newer dual
COX/LOX inhibitors have been studied for human
application, with one, tepoxalin, entering the veterinary
market. Still, there is no evidence to date that such drugs
have greater clinical efficacy and safety than pure COX
inhibitors.
Prostaglandins and inflammation
Prostaglandins and leukotrienes do not cause pain
directly but both cause hyperalgesia. Hyperalgesia is a
pain response to stimuli that are not normally painful,
induced by the lowering of the nociceptor threshold
level. Prostaglandins act as mediators of inflammation
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