Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 13 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CHONDROPROTECTIVE AGENTS
100
80
deracoxib COX-2
deracoxib COX-1
Enzyme inhibition (%)
60
40
20
D
0
0.001
0.01
0.1 1
Concentration (µM)
10
100
1000
100
80
firocoxib COX-2
firocoxib COX-1
Enzyme inhibition (%)
60
40
20
E
0
0.001
0.01
0.1 1
Concentration (µM)
10
100
1000
Fig. 13.2, cont’d
may influence the degree of safety of NSAIDs include
the degree of acidity of any prodrug, the plasma halflife,
the degree of enterohepatic recycling and the potential
for polymorphism in metabolism. One example of
this is found with the human drug celecoxib when used
in dogs. It has been shown that beagle dogs exhibit
polymorphism in the cytochrome P450 system that
leads to some dogs metabolizing celecoxib rapidly and
others slowly. Another example relates to gastrointestinal
ulcers and ulcer healing. Inhibition of COX-1 is
associated with a greater propensity for ulcer formation,
suggesting that COX-2 selective drugs reduce the risk
of ulcer formation. However, existing ulcers have
increased COX-2 in the ulcer margin and model studies
have demonstrated that COX-2 inhibition delays healing
of these ulcers. Most of these studies have included
complete inhibition of the COX-2 enzyme, so more
work remains to understand if thresholds or time courses
for the level of inhibition and delayed healing exist.
Non-COX-related mechanisms of action
A relatively new approach in small animal practice is the
use of dual COX/LOX inhibitors. This target has been
active for a while in human medicine; however, no compounds
have come to market yet. The concept is to
inhibit lipoxygenase and the formation of leukotrienes.
Leukotrienes are inflammatory, active in a number of
tissues and have a negative effect on the microcirculation
of gastrointestinal mucosa, leading to a loss of the protective
mucosal barrier. It is thought that inhibition of
LOX helps preserve mucosal integrity, is antiinflammatory
and, in conjunction with inhibition of
COX, provides analgesia comparable to other NSAIDs.
Inhibition of prostaglandin synthesis may only
partially explain the therapeutic effects of NSAIDs. As
well as their peripheral anti-inflammatory actions,
some NSAIDs may also have a central component to
pain relief and even have centrally mediated antiinflammatory
actions. Most NSAIDs, however, cross
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