V Vol. 22, No.
2 February 2000
CE Refereed Peer Review
FOCAL POINT
★Early and proactive treatment
of acetaminophen overdose can
result in a successful outcome
in veterinary patients.
KEY FACTS
■ The toxic dose of acetaminophen
is 10 mg/kg in cats and 150 to
200 mg/kg in dogs.
■ Cats have deficiencies in
glucuronide and sulfate
conjugation that contribute
to acetaminophen toxicity.
■ Cats are more susceptible to
methemoglobinemia and Heinz-
body anemia, whereas dogs are
more prone to hepatic necrosis.
■ Precursors of glutathione
synthesis, such as
N-acetylcysteine, are essential
for treatment of acetaminophen
toxicity.
Acetaminophen
Toxicity in Cats
and Dogs
Tufts University
Nancy S. Taylor, DVM
Nishi Dhupa, BVM, MRCVS
ABSTRACT: Acetaminophen toxicity continues to occur in veterinary patients. Dogs are more
prone to the hepatic necrosis that occurs with such toxicity, whereas cats are more prone to
methemoglobinemia and Heinz-body anemia. The primary goal of treatment is to decrease for-
mation of the reactive intermediate N-acetyl-para-benzequinoneimine. In addition to reviewing
acetaminophen toxicity, this article provides insight into the mechanism for hepatic necrosis
and methemoglobin development and discusses postmortem changes, treatment regimens,
and differences in toxicity between cats and dogs.
A
cetaminophen is a widely accepted nonnarcotic analgesic and antipyretic
drug in human medicine. This agent has largely replaced salicylates be-
cause of the reduced risk for gastric ulceration and inhibition of platelet
adhesion or aggregation. However, although it is considered safe in humans, acet-
aminophen can be toxic and is often fatal in small animals.1 According to experi-
mental data and case reports, cats can be poisoned by as little as 10 mg acet-
aminophen/kg.2 Acetaminophen is considered toxic in dogs at doses between
150 mg/kg and 200 mg/kg, and dogs usually show clinical signs after oral doses
of 200 mg/kg or more.3
Although it is most readily recognized by the trade name of Tylenol® (McNeil
Consumer Health Care, Fort Washington, PA), acetaminophen is the major in-
gredient of most aspirin-free pain relievers and cold remedies. Phenacetin is an-
other source of acetaminophen. In healthy individuals, 75% to 80% of adminis-
tered phenacetin is rapidly metabolized to acetaminophen. Phenacetin can be
formulated alone or as aspirin-phenacetin-caffeine tablets. In Great Britain, acet-
aminophen is known as paracetamol.1
The American Society for the Prevention of Cruelty to Animals Poison Con-
trol Center indicates that from 1992 to 1997 their poison control center re-
ceived 232 calls about cats and 1232 calls about dogs having ingested acet-
aminophen or some type of acetaminophen-containing substance. In 95% of the
cases, owners intentionally gave the acetaminophen to their pets.
Toxicosis in cats most often results from administration by the owner for relief
of pain, fever, and nonspecific ailments3; dogs, however, more often accidentally
Compendium February 2000
Figure 1—The three pathways of acetaminophen metabolism in the liver.
ingest tablets that are not stored properly.3 In these cas-
es, much larger doses, up to 15 to 20 tablets (7500 to
10,000 mg), are absorbed.
METABOLISM AND MECHANISM OF TOXICOSIS
Dogs can tolerate up to 15 mg of acetaminophen/kg
three times daily1; cats, however, are extremely sensitive
to acetaminophen, even at doses that could be consid-
ered safe for analgesia. The difference in toxicosis be-
tween these two species is related to the difference in
metabolism.
Acetaminophen is primarily metabolized in the liver
via three competing pathways (Figure 1). Acetamino-
phen conjugates to a sulfate compound by phenol sul-
fotransferase or to a glucuronide compound by uridine
diphosphate (UDP)–glucuronosyltransferase; in addition,
it can be transformed and oxidized by the cytochrome
P-450 oxidative process that converts acetaminophen
to an electrophilic reactive intermediate known as
N-acetyl-para-benzequinoneimine (NAPQI).4 The toxic
effects of acetaminophen are related to the formation of
NAPQI.1–5
The amount of acetaminophen transformed by the
cytochrome P-450 oxidative process is initially mini-
mal. Metabolites from glucuronide and sulfate conjuga-
tion are nontoxic and are excreted readily into the bile
and urine along with other minor metabolites and a
small amount of nontransformed acetaminophen. Re-
duced glutathione usually conjugates with the reactive
HALF-LIFE ■ GLUCURONIDE CONJUGATE ■ SULFATE CONJUGATE
Small Animal/Exotics
metabolite, NAPQI, which
is converted into a nontox-
ic product of cysteine and
mercapturic acid that can
be excreted into urine6 (Fig-
ure 1). Glutathione conju-
gation with NAPQI may
be protective at low doses
of acetaminophen; howev-
er, further exposure can
deplete glutathione stores
and facilitate build-up of
the toxic metabolite.4,6
A few important factors
play a role in acetamino-
phen toxicity. Acetamino-
phen saturates the sulfate
and glucuronide conjuga-
tion pathways, thereby
prolonging the half-life of
acetaminophen and result-
ing in continued high con-
centrations for longer peri-
ods. When these pathways
become saturated, the quantity of NAPQI increases.
In dogs, the half-life of acetaminophen is 1.2 hours
at a dose of 200 mg/kg but increases to 3.5 hours at a
dose of 500 mg/kg.4 The major metabolite in dog urine
is the glucuronide conjugate (75%), followed by the
sulfate conjugate (10% to 20%) and the cysteine con-
jugate (5%).4
In cats, the half-life of acetaminophen is 0.6 hours at
a dose of 20 mg/kg but increases to 2.4 hours at a dose
of 60 mg/kg.4 The major metabolite of acetaminophen
at doses of 20 mg/kg in cats is the sulfate conjugate
(90%), followed by the cysteine conjugate (5%) and
the glucuronide conjugate (1%).4 Although the major
pathway for acetaminophen conjugation in cats is
through sulfate binding, sulfate is limited in cats. Cats
also have lower UDP–glucuronosyltransferase activity
in the liver; therefore, glucuronide is less available for
conjugation.4 The deficiency in acetaminophen-direct-
ed UDP–glucuronosyltransferase activity, coupled with
the limited capacity for sulfate conjugation, causes a
prolonged half-life of acetaminophen in cats at much
lower doses than in dogs.7,8 Compared with dogs, cats
have a limited (1⁄10) capacity to eliminate acetamin-
ophen.4 This limitation results in significant formation
of the highly reactive metabolite NAPQI. Recent stud-
ies have isolated the genetic defect in cats that produces
a nonfunctional pseudogene to UDP–glucuronosyl-
transferase.
Another important factor in acetaminophen toxicosis
Small Animal/Exotics
is that, together with increases in cytochrome P-450
oxidation, use of reduced glutathione is raised to the
point at which cellular stores become depleted. Re-
duced glutathione is the main endogenous reducing
agent and defense against electrophilic xenobiotics.
When NAPQI can no longer be inactivated by the liv-
er, it becomes free to react with hepatic proteins by co-
valent bonding.9 This results in hepatocellular damage,
which is often a sequela of acetaminophen toxicosis.
Depletion of protective glutathione stores in eryth-
rocytes also predisposes these cells to oxidative stress
induced by NAPQI.9 This stress results in methemo-
globinemia and Heinz-body anemia, which lead to oxy-
gen deprivation in tissue and the clinical signs of shock
(tachycardia, decreased blood pressure, and poor perfu-
sion).
TOXIC EFFECTS OF ACETAMINOPHEN
At toxic doses, acetaminophen often causes hepatic
necrosis, especially in dogs. Methemoglobinemia and
Heinz-body anemia are more common in cats but can
also occur in dogs.
Hepatic Necrosis
Studies have shown a direct correlation among the
extent of covalent bonding to hepatic proteins, the rate
of hepatic glutathione depletion, and the susceptibility
of a species to hepatotoxicity.10–12
The exact mechanism of liver necrosis continues to
be debated. Studies have shown that high doses of acet-
aminophen cause morphologic changes in mitochon-
dria. Mitochondrial dysfunction occurs early in the
course of acetaminophen hepatotoxicity and is caused
by an inhibition of mitochondrial respiration as soon as
1 hour after ingestion and well before overt toxicity oc-
curs. Morphologic changes seen in the mitochondria,
such as swelling and enlargement, also occur early.11
One hypothesis holds that, by covalently binding to
critical proteins in the mitochondria, NAPQI triggers
the disruption of a critical cellular function or pathway.
This disruption results in morphologic changes and in-
hibition of mitochondrial respiration and, in turn,
leads to cell death and necrosis.11 One study isolated a
mitochondrial protein that was bound with NAPQI
0.5 hour after a toxic dose of acetaminophen was given.
The protein seems to be glutamine dehydrogenase, a
key enzyme in carbon and nitrogen metabolism.
Whether this binding affects the nitrogen–carbon
metabolism in the cell and whether such binding is im-
portant in acetaminophen toxicity is a key question
that has yet to be answered.12
Another proposed theory for the mechanism of hepa-
totoxicity is oxidative stress. NAPQI depletes the cell of
HEPATOTOXICITY ■ MITOCHONDRIAL DYSFUNCTION ■ OXIDATIVE STRESS
Compendium February 2000
glutathione, which is normally protective against oxida-
tive stress.
Oxidative stress is generally associated with produc-
tion of reactive oxygen species (i.e., hydrogen peroxide,
superoxide anion, and the highly reactive hydroxyl rad-
ical), which may lead to glutathione oxidation, lipid
peroxidation, DNA damage, and protein oxidation.13 It
has been suggested that the administration of antioxi-
dant agents may prevent acetaminophen toxicity. How-
ever, in vivo studies of oxidative stress and hepatotoxici-
ty are inconclusive and contradictory.13
Increased cytosolic calcium levels have also been im-
plicated in cell death. However, the increase in calcium
levels lagged behind cell injury. Calcium may exacer-
bate the problem of liver damage as a secondary rather
than an initial cause of cell injury.14,15
Recent studies have examined the role of leukocytes
in acetaminophen-related liver necrosis. The effects of
tumor-necrosis factor on neutrophils are vascular plug-
ging and macrophage induction, and it has been con-
cluded that these effects play a role in the progression
of liver damage but are not the inciting cause.16
Methemoglobinemia and Heinz-Body Formation
Methemoglobinemia is a common sequela of acet-
aminophen toxicity. Methemoglobin formation is the
first manifestation of oxidative stress in erythrocytes.
Glutathione is an essential antioxidant in erythrocytes
and protects against methemoglobinemia.2 Increased
doses of acetaminophen lead to depletion of glu-
tathione, leaving the erythrocytes unprotected from the
oxidizing effects of NAPQI.2 Cats are more prone to
oxidation than are dogs because feline hemoglobin has
eight reactive sulfa hydroxyl groups, whereas canine
hemoglobin has only four.2,17 Thus, methemoglobine-
mia is more commonly associated with acetaminophen
toxicity in cats than in dogs.
As glutathione levels decrease, methemoglobin is
formed from hemoglobin by oxidation of iron from the
ferrous to the ferric state. Methemoglobinemia occurs
when the rate of formation of methemoglobin exceeds
the ability of the reductase system to keep methe-
moglobin in the reduced state. Methemoglobin is inca-
pable of transporting oxygen and pushes the oxyhe-
moglobin curve to the left, making it more difficult to
unload oxygen to the tissues. This results in the clinical
signs associated with tissue hypoxia.18 Methemoglobin
can be measured by a co-oximeter or at a local human
hospital.
A small amount of methemoglobin (0.5% to 3.0% of
the total hemoglobin) is normally found in blood.3
Clinical signs begin to appear as soon as the hemoglo-
bin comprises 20% methemoglobin.3 Coma and death
 Compendium February 2000 Small Animal/Exotics

Clinical Signs of have been observed when edema of the face, paws, and forelimbs have been re-
the methemoglobin percent- ported.3
Acetaminophen Toxicity age exceeds 80% of the total In dogs, signs associated with centrilobular hepatic
Methemoglobinemia hemoglobin.3 necrosis are most commonly seen, usually within 24 to
The formation of Heinz 36 hours after acetaminophen overdose.3 In cats, hepat-
■ 0 to 24 hours
bodies occurs as a complica- ic necrosis is not a common occurrence, although in-
Chocolate-brown tion of acetaminophen toxic- creases in serum alanine aminotransferase and aspartate
mucous membranes ity. Methemoglobin forma- aminotransferase have been reported. Icterus, if seen,
Tachycardia tion can lead to denaturation usually appears in a secondary phase 24 to 48 hours af-
Dyspnea of hemoglobin as a result of ter administration of acetaminophen and may result
Cyanosis exhaustion of the methe- from hepatic necrosis, intravascular hemolysis, or both.3
moglobin reductase system.2 Signs of hepatic necrosis are usually seen 24 to 48
Depression
Heinz bodies are formed hours after ingestion of a toxic dose of acetaminophen.
Vomiting from precipitation of the dam- Early signs of hepatopathy may be a painful abdomen
aged hemoglobin in erythro- and increased levels of alanine aminotransferase and as-
■ 12 to 24 hours cytes. The presence of Heinz partate aminotransferase. As necrosis progresses, hypo-
Edema of face, neck, bodies leads to an increase in glycemia, icterus, hepatoencephalopathy, coagulation
and limbs osmotic fragility of erythro- disorders, and death ensue.
cytes, erythrocyte hemolysis,
Conjunctival edema
and anemia.17 POSTMORTEM CHANGES
Hypothermia Microscopic hepatic lesions are more severe in dogs
Ataxia CLINICAL SIGNS AND than in cats. The livers of dogs with acetaminophen
Coma LABORATORY FINDINGS toxicosis show diffuse centrilobular necrosis and con-
Signs of toxicity (see Clin- gestion, hydropic degeneration, and biliary stasis. One
Liver Failure ical Signs of Acetaminophen study reported the presence of proteinaceous tubular
Toxicity) may be seen as soon casts, renal congestion, and nephrosis in dogs.6
Painful abdomen
as 1 to 4 hours after drug in-
Elevated liver enzymes gestion but usually occur
Hypoproteinemia within 6 to 24 hours. 3 In • Easy Reference Index
Icterus cats, clinical signs include Emergency Medicine • 364 Pages
chocolate-brown mucous in Small Animal Practice • Color and
Hypoglycemia Black-and-White
Coagulopathy membranes (Figure 2A), Photographs
which is typical of methe- ✶ Cardiac Emergencies
Encephalopathy ✶
moglobinemia2; cyanosis of Trauma
the buccal mucosa (Figure ✶ Shock Emergency
✶ Seizure-related Medicine
2B); dyspnea; and tachycar- Disorders
dia. These signs are caused by tissue hypoxia and may ✶ Toxicology
sometimes be associated with vomiting. Edema of the ✶ Thermal Emergencies
face, neck, and limbs (Figures 2C, 2D, and 2E) is also and much more
frequently reported 12 to 48 hours after acetamino-
ff!
phen overdose. Depression; hypothermia; ataxia; con-
junctival edema; and dilated, nonresponsive pupils are
10% o $
61 in Small A
nimal Prac
tice
00
occasionally reported. Less commonly seen signs in-
clude hypersalivation, hyperesthesia, and convulsions.
Coma indicates a poor prognosis.3
$
68 COLLE
The
COMPENDIUM
CTION

In dogs, acetaminophen poisoning causes both

methemoglobinemia and hepatic necrosis. With a sin-
gle dose of 200 mg/kg, clinical signs are similar to
those described in cats.3 The intensity and duration of
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20%.3 At higher methemoglobin levels, vomiting and

HEINZ BODIES ■ TISSUE HYPOXIA ■ HEMOGLOBINURIA

Small Animal/Exotics
Figure 2A
Figure 2C
Figure 2E
Figure 2—Clinical manifestations of acetaminophen toxicity
in cats. (A) Chocolate-brown mucous membranes, typical of
methemoglobinemia. (B) Cyanotic mucous membranes. (C)
Facial edema. (D) Same cat as in Figure 2C after successful
treatment of acetaminophen toxicity. (E) Limb edema. (Fig-
ures 2C, 2D, and 2E courtesy of L. R. Aronson)
EDEMA ■ PERICHOLANGITIS ■ BILIARY STASIS
Compendium February 2000
Figure 2B
Figure 2D
Diffuse centrilobular necrosis is not usually seen in
cats, but peripheral hepatic degenerative changes do oc-
cur. Pericholangitis, mononuclear cell infiltrates, moderate
bile duct proliferation, biliary stasis, and vacuolated
hepatocytes are seen. Kidney lesions are uncommon in
cats.6 One theory for the lack of hepatic necrosis in cats
with acetaminophen toxicosis is that they die of hypox-
ia secondary to methemoglobinemia at doses that are
too low to produce hepatic necrosis.3
TREATMENT
The goals of treatment (see Treatment for Acetamin-
ophen Toxicosis) generally are to decrease absorption of
acetaminophen from the gastrointestinal tract, hasten
elimination of unchanged acetaminophen, limit forma-
tion of NAPQI, and provide supportive care to correct
dehydration and acid–base and electrolyte abnormali-
ties; specific treatment is aimed at restoring glutathione
stores, eliminating methemoglobin, and improving oxy-
gen delivery to tissues.19,20
On presentation, the animal should be given supple-
Small Animal/Exotics Compendium February 2000

mental oxygen. Handling must be kept to a

minimum to reduce stress for the animal. In-
travenous fluid therapy should be started to
promote diuresis for elimination of the toxin. ■ Provide supplemental oxygen.
Hypovolemic patients may benefit from sub- ■ Minimize handling.
stantial fluid loading. ■ Administer various fluids, drugs, and supportive agents.
If an animal is presented immediately after
ingesting acetaminophen, vomiting can be in-
duced. Introduction of a stomach tube and
gastric lavage can also be useful. However, be-
cause acetaminophen is rapidly absorbed, gas-
tric lavage may not be beneficial for more
than a few hours following exposure.20 In ad-
dition, the procedure may be too stressful for
a severely compromised, hypoxic patient.
■ Monitor for liver failure and treat as necessary.
Although these patients require glutathione
replacement, provision of exogenous glu-
tathione was found to be ineffective because
glutathione is normally synthesized in situ and
does not effectively penetrate intact cells. At-
tention should therefore be turned to admin-
istration of glutathione precursors that readily
■ Monitor for coagulopathy and treat as necessary.
enter cells and facilitate an increased rate of
glutathione synthesis in vivo.1
Glutathione requires three amino acids for
its synthesis: cysteine, glutamine, and glycine.
Because many metabolic pathways readily
produce glutamine and glycine, attention has
focused on providing cysteine to the patient.1
N-acetylcysteine is rapidly hydrolyzed to cys-
teine in vivo and functions by providing avail-
able cysteine for the increased synthesis of glu-
tathione. In addition, research has shown that
N-acetylcysteine directly interacts with the reactive
metabolite of acetaminophen to form a nontoxic
acetylcysteine conjugate.1 However, repletion of cys-
teine is believed to play only a minor role in therapy.
Repletion of glutathione stores allows NAPQI to be
converted to a nontoxic metabolite, thus protecting the
patient from ongoing methemoglobin production and
hepatic necrosis.1,2
N-acetylcysteine has also been shown to increase con-
centrations of free serum sulfate in rats with acetamino-
phen toxicosis21; this allows more substrate for the sul-
fate conjugation pathway and may be especially helpful
in cats because of their limited capacity for sulfate con-
jugation. N-acetylcysteine is administered as follows:
23% N-acetylcysteine and 5% dextrose are diluted in
water to make a 3% solution. A loading dose of 140 mg
N-acetylcysteine/kg is given through a peripheral intra-
venous catheter for 1 hour using an in-line 0.2-micron
millipore filter22,23; a 70 mg/kg dose is then given intra-
venously or orally every 6 hours for seven treatments.1,2
Treatment for Acetaminophen Toxicosis
Intravenous fluids (to maintain mean arterial pressure
above 80 mm Hg and to promote diuresis)
N-acetylcysteine: loading dose of 140 mg/kg
intravenously, then 70 mg/kg intravenously or orally
every 6 hr for seven more treatments
Cimetidine: 5 mg/kg intravenously three times daily
Vitamin C: 30 g/kg intravenously four times daily
Lactulose: 1 to 3 ml/kg orally four to six times daily
Neomycin/metronidazole: 15 mg of neomycin/kg as an
enema four times daily or 10 to 20 mg/kg orally four
times daily; 20 mg of metronidazole/kg orally three
times daily or 10 mg/kg intravenously three times daily
Fresh-frozen plasma: 10 ml/kg intravenously
Glucose: 0.5 to 1 ml/kg 50% dextrose intravenously as
needed to maintain blood glucose below 40 mg/dl, then
2.5% to 5% dextrose added to intravenous fluids
Vitamin K: 2.4 mg/kg subcutaneously two to three times
daily
Blood products: as needed
N-acetylcysteine treatment seems to be less effica-
cious when it is initiated more than 8 hours after inges-
tion of acetaminophen20 but can still be somewhat effi-
cacious 36 to 80 hours after ingestion.20 Studies have
shown that N-acetylcysteine treatment prevented hepa-
totoxicity in humans presenting within 8 hours of in-
gestion of acetaminophen (regardless of the dose).
When N-acetylcysteine therapy was initiated within 10
hours of exposure, hepatotoxicity occurred in 26% of
cases; hepatotoxicity occurred in 41% of patients treat-
ed 10 to 24 hours after ingestion.20
N-acetylcysteine may also be useful for decreasing
methemoglobin formation in erythrocytes because of its
ability to form glutathione. Glutathione is known to di-
rectly reduce endogenous methemoglobin,22 and N-ace-
tylcysteine may also reduce methemoglobin by altering
drug metabolism. By forming glutathione, N-acetylcys-
teine may favor formation of nontoxic instead of reac-
tive intermediates; it may also act as a reducing agent for
intermediate free radicals. In summary, N-acetylcysteine

GASTRIC LAVAGE ■ GLUTATHIONE SYNTHESIS ■ N-ACETYLCYSTEINE

Small Animal/Exotics
may be beneficial in reducing methemoglobin forma-
tion by causing direct reduction of the heme molecule,
metabolic shunting of xenobiotic agents to metabolic
pathways in which an oxidative agent is not formed,
and reduction of the oxidizing agent itself.22
Use of activated charcoal is controversial. It binds
with acetaminophen but, when given orally, also binds
with N-acetylcysteine, thereby inhibiting the effects of
N-acetylcysteine. In dogs and cats that are depressed
and vomiting, administration of activated charcoal may
exacerbate the vomiting and lead to aspiration.20
In humans, hemodialysis removed about 10% of an
ingested dose of acetaminophen but was not shown to
change clinical outcome and was not recommended.20
Peritoneal dialysis would also be unlikely to change the
outcome for dogs or cats.
Cimetidine has been suggested for the treatment of
acetaminophen overdose because of its ability to inhibit
the cytochrome P-450 oxidation and therefore the for-
mation of NAPQI. Cimetidine is believed to lessen
hepatotoxicity and can be an additive therapy to N-
acetylcysteine.24 Although some studies have shown de-
creased oxidation with cimetidine, others have shown
no effect.25 Because of the mechanism of action, cimeti-
dine would need to be given very early in the course of
toxicity to be effective. Even with large doses of cimeti-
dine, complete inhibition of the cytochrome P-450 sys-
tem does not occur24; therefore, it should only be used
as an adjunct to therapy. The recommended dose is 5
mg/kg administered intravenously every 8 hours.26
Vitamin C can be used in the treatment of acet-
aminophen toxicity because of its antioxidant proper-
ties.2 It is used to alleviate methemoglobinemia and can
supplement the endogenous protective mechanism of
glutathione to prevent covalent binding of reactive acet-
aminophen metabolites.1 The recommended dose is 30
mg/kg administered intravenously four times a day.2
Blood transfusions should be administered as needed
for anemia, and guidelines for blood transfusion may
need to be altered. Checking for signs of hypoxemia
should be done rather than monitoring the hematocrit
because the hematocrit is not a true reflection of the
oxygen-carrying capacity in the presence of methemo-
globinemia.
The treatment for coagulopathy in hepatic failure can
be complex. Treatment for this disorder is discussed
briefly in Treatment for Acetaminophen Toxicosis, and
readers are referred to other sources for further infor-
mation.25,26
Infection secondary to gastrointestinal bacterial
translocation can also occur in hepatic failure because
the liver has a reduced ability to clear translocated bac-
teria. Two controlled studies in humans have shown a
ACTIVATED CHARCOAL ■ CIMETIDINE ■ VITAMIN C ■ LACTULOSE
Compendium February 2000
benefit of prophylactic antibiotics in fulminant hepati-
tis.25 Such broad-spectrum antibiotics as cefazolin or
ampicillin (20 mg/kg administered intravenously every
8 hours) can be given.
Lactulose (1 to 3 ml/kg every 4 to 6 hours adminis-
tered intravenously or via an enema) can also be used
for the treatment of hepatoencephalopathy.26 Hypo-
glycemia in liver failure is caused by impaired gluco-
neogenesis, prolonged insulin half-life, and impaired
mobilization of glycogen stores. Serum glucose levels
should be monitored regularly and intravenous glucose
provided by dextrose solutions as necessary.25
FUTURE THERAPIES
Future directions in therapy may be suggested by
new studies. One study has shown that dietary supple-
mentation of glutamine helped replenish glutathione
stores in rats given toxic levels of acetaminophen.24
In another study, researchers compared the effects of
acetylcysteine and prostaglandin E2 when given to rats
30 minutes after administration of a toxic dose of acet-
aminophen. Prostaglandin E2 is believed to be cytopro-
tective. It was found that serum alanine aminotrans-
ferase levels were near normal in the prostaglandin
group 24 hours after the acetaminophen exposure but
were still nine times higher than normal in the N-acetyl-
cysteine group. Histopathologic hepatic injury was also
markedly reduced in the prostaglandin group.20, 24
SUMMARY
Although acetaminophen is still a problem in veteri-
nary patients, much is known about the pathophysiolo-
gy of toxicosis and the treatment for this potentially
deadly toxin. The toxic effects of acetaminophen are re-
lated to formation of NAPQI by the cytochrome P-450
system when normal sulfate and glucuronide pathways
are saturated or when glutathione becomes depleted.
Glutathione is important for cell protection; when de-
pleted, damage to the liver and erythrocytes occurs,
leading to liver necrosis and methemoglobinemia, re-
spectively.
Signs of acetaminophen toxicity are similar between
cats and dogs. However, centrilobular necrosis seems to
be more prominent in dogs, whereas methemoglobine-
mia and Heinz-body anemia are more common in cats.
Acetaminophen toxicity is dose dependent. As little
as 10 mg/kg in cats or 150 to 200 mg/kg in dogs is
considered toxic. Treatment can be successful if initiat-
ed early enough. The key to therapy is the provision of
precursors for glutathione production. N-acetylcysteine
is essential in the treatment of acetaminophen toxicosis
because it provides cysteine for synthesis of glutathione
and also reacts with NAPQI to form a nontoxic conju-
Compendium February 2000
gate. Cimetidine and vitamin C are both helpful when
used in conjunction with N-acetylcysteine. Intravenous
fluids, oxygen supplementation, blood products (if re-
quired), and treatment of liver disease are also crucial.
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versus oxidative stress. Chem Res Toxicol 9:580–585, 1996.
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About the Authors
When this article was submitted for publication, Drs. Taylor
and Dhupa were affiliated with the Department of Medi-
cine, School of Veterinary Medicine, Tufts University, North
Grafton, Massachusetts. Dr. Taylor is currently affiliated
with Puget Sound Pet Pavilion, Tacoma, Washington.