Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 13 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CHONDROPROTECTIVE AGENTS
and is clinically insupportable, particularly when such
drugs are used concurrently with corticosteroids.
There continues to be debate regarding the possible
beneficial role that NSAID use may have in treatment
of septic and endotoxic shock. The efficacy of some
NSAIDs, especially flunixin, in endotoxic shock in
horses and dogs has been demonstrated but the drug
must be administered prior to or immediately after the
onset of endotoxemia.
Renal toxicity
A second potential side effect of NSAIDs is renal toxicity
following reduced renal blood flow and glomerular
filtration rate secondary to inhibition of renal prostaglandin
synthesis. Immunohistochemical staining of
kidney tissue has revealed the presence of both COX-1
and COX-2. Renal prostaglandins are involved in maintaining
renal blood flow via their vasodilatory actions.
In a healthy, well-hydrated animal, reduced renal prostaglandin
production is of little consequence. However,
significant renal toxicity can result if an animal is volume
depleted, is avidly retaining sodium (e.g. in congestive
heart failure or hepatic cirrhosis) or has pre-existing
renal insufficiency. Renal toxicity with NSAIDs has
been described in humans and horses but has not been
well documented in dogs and cats. However, a recent
study demonstrated that creatinine clearance was significantly
lower in dogs given carprofen or ketoprofen
at induction of anesthesia compared to controls given
saline.
When the sympathetic and renin-angiotensin systems
are activated by sodium depletion, volume depletion or
systemic hypotension, noradrenaline (norepinephrine)
and angiotensin II act as potent vasoconstrictors, which
may reduce renal blood flow, especially in the medulla.
PGI 2 in the glomerulus and PGE 2 in the medulla counteract
the vasoconstrictor actions of noradrenaline (norepinephrine)
and angiotensin II and therefore protect the
kidney from ischemic damage. Production of PGI 2 and
PGE 2 is stimulated by vasoconstrictive substances. If the
production of these protective prostaglandins is blocked
by NSAID administration, renal failure may result.
The potential for renal toxicity to occur in a volumedepleted
dog is a further potent reason why NSAIDs
should not be administered to any animal in shock posttraumatically
or to any animal that may have significant
gastrointestinal disease resulting in dehydration and
volume depletion. As discussed above, selective COX-2
inhibitors may not prove to be safer than nonselective
NSAIDs in the volume-depleted dog.
Hepatotoxicity
Hepatic toxicity is uncommon in animals receiving
NSAIDs; however, there have been recent reports of
idiosyncratic hepatotoxicity associated with carprofen
use in dogs. Idiosyncratic hepatic toxicity, although
rare, has been associated with the use of most classes of
NSAIDs in humans. Hepatic toxicity has been associated
with the use of phenylbutazone in aged horses but
has not been reported in dogs. Paracetamol (acetaminophen)
overdose can cause serious hepatocellular damage
in dogs and adult humans but, interestingly and inexplicably,
this occurs less often in cats and human infants.
However, the therapeutic margin of paracetamol is low
in cats where it causes methemoglobinemia, anemia and
other signs.
Adverse effects on hematology and hemostasis
Prolongation of bleeding times due to inhibition of
platelet thromboxane production can potentially occur
after administration of NSAIDs, although at dose rates
used clinically most NSAIDs do not impair hemostasis.
This may be due to the fact that COX-1 blockade of
thromboxane production is balanced by COX-2 inhibition
in endothelial cells, resulting in reduced release of
PGI 2 which normally causes vasodilation and reduced
platelet aggregation. However, bleeding may occur with
the use of drugs that irreversibly bind to COX-1, such
as aspirin and phenylbutazone, as the effect persists for
the life of the platelet (which is unable to synthesize
additional thromboxane as it lacks a nucleus). Studies
with more COX-2 selective drugs, such as carprofen,
deracoxib and firocoxib, have not shown prolongation
of bleeding time, in some cases even at high dosages.
Thromboxane is a potent vasoconstrictor and stimulus
for platelet aggregation and the reduced vasoconstriction
and platelet aggregation that occur may be
significant in patients with bleeding tendencies or may
complicate surgical procedures. NSAIDs should be used
with extreme care in breeds, such as dobermans and
Scottish terriers, that have a high incidence of von
Willebrand’s disease.
Myelotoxicity (agranulocytosis) occurs relatively
commonly in humans but is rare in dogs. Blood dyscrasias
have been reported occasionally in association with
the use of phenylbutazone in dogs.
Human use of coxibs and even some nonselective
NSAIDs has been associated with an increased risk of
cardiovascular events, particularly stroke and heart
attack. Several theories have been proposed to explain
this potential. These include a drug-related increase in
blood pressure, unbalanced inhibition of prostacyclin
and thromboxane and drug-dependent oxidative damage
to low-density lipid which causes vascular inflammation.
Although still under investigation, the strongest
theory relates to coxibs not being platelet inhibitors. In
this manner, they do not inhibit thromboxane and the
propensity for clot formation is increased. At the same
time, they inhibit prostacyclin which plays a role in
modulating the effects of thromboxane. In a large-scale
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