Page 405 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

372 SECTION | IV Drugs of Use and Abuse

VetBooks.ir deficient in cats, limiting their elimination of salicylate. above. Aspirin allows penetration of H across the mito-
Aspirin uncouples oxidative phosphorylation, as noted
1
Bismuth subsalicylate is metabolized to bismuth and
salicylate in the gastrointestinal tract (Boothe, 2001).
chondrial membrane, thus disrupting the proton gradient.
The kidneys eliminate salicylate and its glycine conju- The result is inhibition of the enzyme ATP synthetase.
gate (Boothe, 2001). Two to thirty percent of a dose of Energy that would go into ATP production is dissipated
aspirin is excreted as unconjugated salicylate (Verbeeck, as heat. When oxidative phosphorylation is uncoupled
1990). The rate of elimination for aspirin varies with spe- systemically, the result is elevated body temperature
cies and age (McKellar et al., 1991). The elimination (Roder, 2004a).
half-life in dogs is dependent upon the dose form. The Salicylates can produce acidosis and increase the
half-life for enteric-coated products ranges from 7.5 to anion gap. Salicylate and metabolites thereof increase
12.2 h. The elimination half-life for aspirin given IV is the anion gap directly (Schubert, 1984; Kore, 1990).
2.2 8.7 h (Boothe, 2001). The elimination half-life in Anaerobic metabolism compensates for the reduced ATP
cats is long, and increases with dose. If low doses of production when oxidative phosphorylation is inhibited,
5 12 mg/kg are given, the elimination half-life is producing metabolites such as lactic acid, pyruvic acid,
22 27 h, but the half-life for the much higher dose of and ketones, thus contributing to acidosis. Aspirin is also
25 mg/kg is 45 h. Salicylate is considered to have zero- believed to directly stimulate respiratory centers in the
order kinetics in cats (Lees et al., 1991). The elimination CNS, causing hyperventilation and respiratory alkalosis
half-life in horses is about an hour due to ion trapping in and promoting renal secretion of bicarbonate (Kore, 1990;
alkaline urine. Salicylates are normal components of Boothe, 2001). Later in the progression of the toxicosis,
equine urine (Boothe, 2001). The elimination half-life of CNS suppression can decrease the respiratory rate, also
salicylates in cattle is about 30 min (Lees et al., 1991; contributing to acidosis.
Boothe, 2001). Young animals metabolize aspirin more
slowly, and the elimination half-life may be prolonged in
puppies less than 30 days old, piglets, kids, and foals. Clinical Signs
Similar to other NSAIDs, gastric irritation is the most
Mechanism of Action common side effect of aspirin. Vomiting, gastric ulcera-
tion, and hemorrhage are often observed. Depression is
The effects attributed to aspirin are mostly caused by the
also reported in aspirin toxicosis in dogs and cats (Kore,
active metabolite salicylate (McKellar et al., 1991).
1990; Jones et al., 1992). Profound depression has been
Salicylate inhibits COX to block PG synthesis, as
reported in dogs given high doses of aspirin. Affected
described for NSAIDs. Other NSAIDs competitively
dogs have sometimes collapsed or appeared too weak to
inhibit COX, but salicylates permanently inactivate the
stand. Restlessness progressing to tremors, seizures and,
enzyme by acetylating a serine residue (Kore, 1990;
eventually, coma has been observed in dogs (Kore, 1990).
Rubin and Papich, 1990; Boothe, 2001; Talcott, 2006).
One dog had a progressive increase in seizure duration
Platelets are unable to synthesize COX. Unlike other
from 5 to 45 min (Schubert, 1984). Seizures and coma
NSAIDs, where coagulopathy resolves once the drug is
have also been observed in cats (Jones et al., 1992;
eliminated, it takes about 1 week to resolve aspirin-
Isaacs, 1996). Seizures have been attributed to hypoventi-
induced coagulopathy.
lation, acidosis, and hypoglycemia. Aspirin toxicosis can
Aspirin has a direct irritant effect on the gastric
cause hyperthermia in children and cats. There can be an
mucosa. Aspirin is an acidic drug, and is taken up by the
initial hyperpnea in acute aspirin toxicosis due to stimula-
mucosal epithelium, where it becomes concentrated
tion of respiratory centers.
(Carson and Strom, 1988; Rubin and Papich, 1990;
Isaacs, 1996). Aspirin inhibits oxidative phosphorylation
of the gastric mucosal epithelium, thus decreasing ATP
1
production and Na /K 1 movement across the cell mem- Clinical Chemistry and Postmortem Findings
brane and producing cell swelling and necrosis (Rubin Metabolic acidosis and increased anion gap have been
and Papich, 1990). Disruption of ion transport allows noted in acute aspirin toxicosis (Roder, 2004a). Bone
increased H 1 ion back-diffusion into the mucosa. Injury marrow suppression can cause anemia in cats (Kore,
can extend into submucosal capillaries, leading to hemor- 1990; McKellar et al., 1991). Other changes are similar to
rhage, inflammation, and ulceration. IV dosing of cats those described with other NSAIDs. Lesions similar to
produced gastric erosions and ulcers, confirming that other NSAIDs are expected on necropsy. Gastric mucosal
there is also a role for COX inhibition and reduced PG lesions have been documented in the pyloric antrum,
synthesis in the pathophysiology of gastric mucosal body, and cardiac region of the stomach of dogs (Boulay
damage (Villar et al., 1998). et al., 1986).