Page 393 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

360 SECTION | IV Drugs of Use and Abuse

VetBooks.ir endonucleases and DNA fragmentation are proposed therapeutically for acetaminophen toxicosis. Young ani-
mals are sometimes less sensitive to acetaminophen toxi-
causes of cell death. Production of superoxide anions
cosis than mature animals. This is the case in children and
causing peroxidative injury occur during phase I metabo-
lism of acetaminophen, causing oxidative stress in the neonatal mice, and is believed to be due to the immaturity
cell, especially once glutathione has been depleted. of the mixed-function oxidase system and more rapid glu-
Endothelial damage is the likely cause of clinical signs tathione synthesis in these youngsters (MacNaughton,
such as edema of the face and extremities and 2003).
hemorrhage.
PAP, another reactive metabolite, is implicated in the
hematotoxic effect seen in cats and dogs (McConkey Clinical Signs
et al., 2009). Unlike most species, erythrocyte injury is a Clinical signs of acetaminophen toxicosis in cats and dogs
major adverse effect associated with acetaminophen are attributable to its toxic effects on erythrocytes and
ingestion in cats. It is also observed in dogs at high doses, hepatocytes. Clinical methemoglobinemia is the most
although hepatotoxic effects predominate at relatively low common problem in cats, and can also occur in dogs.
doses in dogs. Oxidative injury to the erythrocyte takes the Centrilobular hepatic necrosis is most common in dogs,
form of methemoglobin production or Heinz body produc- also occurring in other species, including cats, humans,
tion (Rumbeiha et al., 1995; Webb et al., 2003; McConkey rats, and hamsters (Hjelle and Grauer, 1986).
et al., 2009). GSH becomes depleted in erythrocytes, and Clinical signs in cats usually occur within a couple of
hemoglobin is oxidized to methemoglobin, which cannot hours of exposure. Anorexia and vomiting are reported in
carry oxygen (Hjelle and Grauer, 1986; Aronson and 35% of cats presenting for acetaminophen exposure, and
Drobatz, 1996). Animals with 30% of their hemoglobin hypersalivation is reported in 24% (Aronson and Drobatz,
converted to methemoglobin show clinical signs and cyano- 1996), and commonly occurs within 2 h of exposure
sis (Rumbeiha et al., 1995). Methemoglobinemia is revers- (Savides and Oehme, 1985). Diarrhea occurred in 18% of
ible through conversion back to hemoglobin by cats. Mental depression is reported in 76%, and usually
methemoglobin reductase (Schlesinger, 1995). Cats have takes place within 3 h.
less methemoglobin reductase activity than other domestic Methemoglobinemia occurs within the 4 h of acet-
species (MacNaughton, 2003). Acetaminophen can produce aminophen ingestion in cats, and is dose-dependent. Cats
methemoglobinemia in dogs as well, but this change has given a dose of 60 mg/kg acetaminophen had 21.7% of
not beenreportedinother species(Hjelle and Grauer, 1986; their hemoglobin converted to methemoglobin, and the
McConkey et al., 2009). methemoglobin concentration in cats dosed with 120 mg/
Heinz body formation is an irreversible change caused kg acetaminophen was 45.5% (Hjelle and Grauer, 1986).
by the precipitation of hemoglobin (Schlesinger, 1995; Clinically evident cyanosis occurs at about 30% methe-
Aronson and Drobatz, 1996). Heinz bodies increase red moglobinemia. Fifty-nine percent of the cats in the
cell fragility and decrease survival time of erythrocytes, Aronson and Drobatz (1996) study had pale or dark
and thus, may cause hemolysis and anemia. Until mucous membranes and respiratory distress, and the blood
recently, it was believed that NAPQI bound to the sulfhy- was brown in 12%. Affected cats were weak and
dryl groups and oxidized hemoglobin (Allen, 2003). depressed (Hjelle and Grauer, 1986; Jones et al., 1992;
However, erythrocytes lack the enzymes to metabolize Allen, 2003), 12% presented comatose, and 18% tachy-
acetaminophen to NAPQI, and circulating NAPQI is cardic (Aronson and Drobatz, 1996). Hemolysis, anemia,
unlikely to be bioavailable to erythrocytes. Another reac- icterus, and pigmenturia have been described, and are
tive metabolite, PAP, was found to oxidize hemoglobin seen within 48 h of exposure. In addition to characteristic
in vitro, and thus, has recently been proposed as the cause methemoglobinemia, edema of the face and forelimbs or
of methemoglobinemia in cats and dogs (McConkey front paws is commonly described in affected cats. Death
et al., 2009). There are eight sulfhydryl groups on feline in cats is usually due to methemoglobinemia, but fatal
hemoglobin, but only four on the hemoglobin of other liver failure can also occur. Hepatic necrosis is most com-
domestic species and two on the human molecule, making monly associated with high-dose exposures, particularly
cat erythrocytes much more prone to oxidative injury in male cats.
(Hjelle and Grauer, 1986; Rumbeiha et al., 1995; Aronson Dogs often vomit soon after ingesting a high dose of
and Drobatz, 1996; Allen, 2003; Sellon, 2006). acetaminophen, which can serve a protective function
Factors that enhance the toxic effects of acetaminophen (Schlesinger, 1995). Severe clinical signs in dogs are usu-
include glutathione depletion due to fasting (Treinen- ally attributable to hepatic necrosis (Hjelle and Grauer,
Moslen, 2001) and induction of P4502E1, as occurs with 1986; Schlesinger, 1995; Sellon, 2006). Signs commence
barbiturate exposure (Sturgill and Lambert, 1997). within 36 h of ingestion, and include nausea and vomit-
Cimetidine inhibits cytochrome P450s, and has been used ing, anorexia, abdominal pain, and depression;