Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

UNAPPROVED NSAIDS USED IN SMALL ANIMAL PRACTICE
Ketorolac
(Toradol ® )
Ketorolac is a cyclized propionic acid NSAID that is
used in humans mainly as a postsurgical analgesic rather
than as an anti-inflammatory. It is not approved for use
in dogs. It is reported to be as effective as morphine for
mild-to-moderate postoperative pain. It is most often
given parenterally, although oral formulations are available.
Longer-term use in humans is associated with a
significant incidence of peptic ulceration and renal compromise.
In veterinary medicine, ketorolac has been
used to control postoperative pain in dogs; it is as effective
as flunixin and more effective than butorphanol or
a low dose of oxymorphone. Its use in dogs has been
associated with significant gastrointestinal toxicity.
Naproxen
(Naprosyn ® , Aleve ® )
Clinical applications
Naproxen is widely used in humans and has been used
for the management of chronic musculoskeletal pain in
dogs although it is not approved for dogs. However, the
incidence of adverse effects is relatively high with its use
and there would appear to be little therapeutic benefit
in using this drug in comparison to other more effective
and safer NSAIDs.
Formulations and dose rates
Naproxen is available in tablet formulation.
DOGS
• Naproxen has been administered chronically to dogs at doses
starting at 5 mg/kg PO on the fi rst day and 2 mg/kg PO q.24 h
or q.48 h thereafter
Mechanism of action – additional information
Naproxen is a member of the propionic acid class of
NSAIDs.
Relevant pharmacokinetic data
Naproxen undergoes extensive enterohepatic recycling
in the dog, resulting in prolonged elimination. The halflife
in dogs is as long as 92 h, in comparison to 8.3 h
for horses and 14–24 h for humans.
Paracetamol (acetaminophen)
(Crocin ® , Panadol ® , Tylenol ® , Calpol ® , etc. and
generics)
Clinical applications
Paracetamol (acetaminophen) is not approved for use in
dogs and cats. It is a para-aminophenol derivative. It
has analgesic and antipyretic actions through presumed
central COX inhibition. Recent reports have suggested
that paracetamol may act by inhibition of 5-HT 3 receptors
and COX-3, the product of a splice variant of
COX-1. It does not inhibit peripheral COX. Although
paracetamol is believed to have no significant antiinflammatory
activity, it has been reported to be as
effective as aspirin in the treatment of musculoskeletal
pain in dogs.
Adverse effects
Adverse effects in dogs are reported to be few because
of the lack of peripheral COX inhibition. Cats, however,
are very sensitive to paracetamol and as little as 46 mg/
kg (e.g. half a 500 mg tablet) can cause toxic signs. The
clinical signs of paracetamol toxicity in cats are edema
of the face (mechanism unknown), cyanosis and methemoglobinemia,
anemia, hemoglobinuria and icterus.
Methemoglobinuria occurs as a result of oxidation of
heme, which allows methemoglobin, which is not
capable of binding oxygen, to accumulate. Oxidized
heme also shifts the oxydissociation curve to the left,
which impairs the unloading of oxygen in tissues,
exacerbating the tissue anoxia. The sulfhydryl-containing
tripeptide, reduced glutathione, is thought to be
important in methemoglobin production. Cat hemoglobin
has at least eight sulfhydryl groups per molecule,
more than are found in other species, which may render
it particularly sensitive to oxidation when glutathione
levels fall.
Intravascular or extravascular hemolysis occurs
because of Heinz body anemia. Heinz bodies are microscopic,
round, refractile structures on the internal aspect
of the erythrocyte membrane. They represent sites of
hemoglobin denaturation due to oxidant injury. Clinical
reports of paracetamol toxicosis in cats suggest that
erythrocyte destruction can occur for up to 3 weeks. In
one cat, hemoglobin casts caused urethral obstruction,
an unusual but potentially fatal sequela.
Icterus in cats with paracetamol toxicity is probably
more likely to result from hemolysis than hepatocellular
necrosis. In contrast to humans and dogs, hepatocellular
necrosis is reported to be of less significance in cats with
paracetamol toxicosis.
It is not understood why hepatic necrosis is less
important in cats than in other species, as high concentrations
of the drug remain in the blood for a long time
and a greater proportion is oxidized. Another anomaly
occurs in humans, where doses high enough to cause
hepatic necrosis in adults cause very little damage in
children.
Paracetamol in all species is metabolized by three
pathways: glucuronidation, sulfation and cytochrome
P450-mediated oxidation. The metabolites of glucuronidation
and sulfation are not toxic but the oxidation
pathway yields a reactive toxic metabolite (thought to
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