Acetaminophen Toxicity in Cats and Dogs

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Acetaminophen Toxicity in Cats and Dogs

Postby malernee » Fri Sep 29, 2006 8:21 pm

Acetaminophen Toxicity in Cats and Dogs

<<Compend Contin Educ Pract Vet 22[2]:160 Feb'00 Review Article
Nancy S. Taylor, DVM; Nishi Dhupa, BVM, MRCVS



Acetaminophen is an increasingly popular analgesic and antipyretic for use in humans but it can be toxic or fatal in small animals. Phenacetin is another source of acetaminophen with 75- 80% of the drug metabolizing to acetaminophen. In the United States Tylenol is the most recognized trade name for acetaminophen but it is the primary ingredient in most aspirin free pain and cold remedies. In Great Britain acetaminophen is known as paracetamol.

The toxic dose in dogs is considered to be 150 -200 mg/kg with dogs generally showing clinical signs at doses of 200 mg/kg or more. Dogs can tolerate up to 15 mg/kg TID but cats are much more sensitive to acetaminophen toxicity due to differences in metabolism between the two species. The toxic dose is 10 mg/kg in cats.

From 1992 through 1997 the Poison Control Center (American Society for Prevention of Cruelty to Animals), received 232 calls regarding acetaminophen toxicity in cats and 1232 calls for toxicity in dogs. The pet's owners administered the drug in 95% of the cases but dogs also often accidentally ingest large quantities of the tablets.

Metabolism and Mechanism of Toxicosis

Acetaminophen is metabolized by the liver via three competing pathways:

1. Conjugation to a sulfate compound by phenol sulfotransferase
2. Conjugation to a glucuronide compound by uridine - diphosphate(UCP)-glucuronosyltransferase
3. Transformation and oxidation by cytochrome P-450 to an electrophilic intermediate N - acetyl- para- benzequinoneimine (NAPQI)
NAPQI formation is responsible for the toxic effects of acetaminophen. The metabolites from glucuronide and sulfate conjugation are nontoxic and are excreted in the urine along with small amounts of unchanged acetaminophen. The amount of cytochrome P-450 transformation is initially minimal but reduced glutathione usually conjugates with the NAPQI which is converted into a nontoxic product of cysteine and mercapturic acid which is excreted in urine. Small amounts of the glutathione - NAPQI conjugation may be protective but with depletion of the glutathione stores the toxic metabolite builds up.

The half life of acetaminophen is different in different species and is prolonged when the sulfate and glucuronide pathways become saturated thereby increasing the quantity of NAPQI.

In dogs 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.

Cats primarily metabolize acetaminophen by sulfate binding but sulfate is limited in cats which also have lower levels of UDP - glucuronosyltransferase (therefore less glucuronide is available for conjugation). The end effect of these differences is that cats have a very limited capacity to eliminate acetaminophen - less than 1/10 of dogs- and this results in significant formation of the highly reactive metabolite NAPQI.

Another significant factor in acetaminophen metabolism is the depletion of stores of glutathione as cytochrome P-450 oxidation increases. Reduced glutathione is the main defense against electrophilic xenobiotics, and when it is depleted NAPQI becomes free to bond to hepatic proteins, resulting in heptatocellular necrosis.

Glutathione stores in erythrocytes are also depleted resulting in oxidative stress induced by NAPQI and leading to methemoglobinemia and Heinz-body anemia. The resulting oxygen deprivation leads to clinical signs of shock: tachycardia, lowered blood pressure and poor perfusion.

Toxic Effects of Acetaminophen

In dogs, the primary adverse effect in acetaminophen toxicosis is hepatic necrosis. Methemoglobinemia also occurs but it is more common in cats.

A. Hepatic Necrosis

The exact mechanism of liver necrosis is unknown but may involve mitochondrial damage, oxidative stress, increased cytosolic calcium and/or the role of leukocytes.

B. Methemoglobinemia and Heinz-Body Formation

Glutathione is an essential antioxidant in erythrocytes, protecting them against oxidative stress. In acetaminophen toxicity glutathione is depleted and the erythrocytes are unprotected from the oxidizing effects of NAPQI. Cats are more prone to methemoglobinemia than are dogs because cats have eight reactive sulfa hydroxyl groups versus the dog's four.

As the glutathione levels fall, iron in hemoglobin is oxidized from the ferrous to the ferric state forming methemoglobin. Methemoglobin is incapable of transporting oxygen pushing the oxyhemoglobin curve to the left thereby making it more difficult to unload oxygen at the tissues. Signs of hypoxia then ensue.

Methemoglobin can be measured at a local human hospital. A small amount (0.5 to 3% of the total hemoglobin) of methemoglobin is found in normal blood but clinical signs occur when the methemoglobin reaches 20% of the total hemoglobin..

Methemoglobin formation leads to denaturation of hemoglobin and Heinz-bodies are formed from precipitation of damaged hemoglobin. The Heinz bodies leads to increased erythrocyte fragility, hemolysis and anemia.

Clinical Signs and Laboratory Findings

Signs of toxicity can occur as soon as 1 to 4 hours post-ingestion but usually occur within 6 to 24 hours.

In cats the following signs occur:

Chocolate brown mucus membranes (typical of methemoglobinemia)
Cyanosis, dyspnea and tachycardia and occasional vomiting caused by tissue hypoxia
Edema of face, neck and limbs (12 to 48 hours post ingestion)
Other signs include: depression, hypothermia, ataxia, conjunctival edema and occasionally dilated, unresponsive pupils.
Coma - indicates poor prognosis
Less common signs: hypersalivation, hyperesthesia and convulsions.
In dogs signs of both hepatic necrosis and methemoglobinemia occur. Clinical signs after a dose of 200 mg/kg are similar to cats and hemoglobinuria may be seen in animals with methemoglobin levels greater than 20%. Vomiting and facial and limb edema have also been reported.

In dogs signs of liver necrosis are commonly seen 24 to 36 hours post-ingestion whereas in cats hepatic necrosis is uncommon (although increased serum alanine aminotransferase and aspartate aminotransferase have been reported). Icterus may occur later in a secondary phase 24 to 48 hours after ingestion and may result from necrosis, hemolysis or both. Animals may exhibit a painful abdomen, increased liver enzymes and with progression, hypoglycemia, icterus, hepatoencephalopathy, coagulation disorders and death.

Postmortem Changes

In dogs, liver necrosis is more common and livers exhibit centrilobar necrosis, congestion, hydropic degeneration and biliary stasis. In one study proteinaceous tubular casts, renal congestion and nephrosis were seen in dogs.

In cats centrilobular necrosis is unusual but peripheral hepatic degeneration does occur along with pericholangitis, mononuclear cell infiltrates, biliary stasis and moderate bile duct proliferation. Kidney lesions are uncommon in cats.


The goals of treatment in cases of acetaminophen toxicity are:

1. Decrease absorption from the GI tract
2. Hasten elimination of unchanged acetaminophen
3. Limit formation of NAPQI
4. Provide supportive care and correct dehydration, electrolyte and acid-base abnormalities
5. Restore glutathione levels
6. Eliminate methemoglobin
7. Improve oxygen delivery to tissues
All animals should be given supplemental oxygen and be handled with a minimum amount of stress. IV fluids are begun (with fluid loading in hypovolemic patients) to promote diuresis.

In humans hemodialysis removed about 10% of acetaminophen but did not change the clinical outcome, therefore peritoneal dialysis in dogs and cats would be unlikely to change the outcome of a toxic ingestion.

If the medication has been recently ingested GI emptying and gastric lavage can help but acetaminophen is rapidly absorbed and the procedure may be too stressful if the patient is severely compromised and hypoxic. Use of activated charcoal is controversial because while it binds to the acetaminophen it also binds to N-acetylcysteine and inhibits its effects.

Repletion of glutathione stores allows the toxic NAPQI to be converted into a nontoxic metabolite, protecting the patient from methemoglobinemia and hepatic necrosis however exogenous glutathione has been proven to be ineffective in treatment. Administration of glutathione precursors helps to increase the rate of glutathione synthesis in vivo.

Three amino acids are required for glutathione synthesis: cysteine, glycine and glutamine. However, the last two amino acids are readily produced by a variety of pathways. Therefore cysteine is the amino acid which is provided to the patient via N- acetylcysteine. N- acetylcysteine is metabolized to cysteine for increased synthesis of glutathione and also interacts with the reactive metabolite of acetaminophen to produce a nontoxic acetylcysteine conjugate.

Repletion of cysteine is believed to play a minor role in therapy but N- acetylcysteine also increases concentrations of free serum sulfate and is especially helpful in cats because of their limited sulfate conjugation capacity.

N- acetylcysteine is administered as follows: 23% N-acetylcysteine and 5% dextrose is diluted in water to make a 3% solution. Using a 0.2 micron millipore filter,140 mg/kg is given as a loading dose during the first hour. A 70 mg/kg dose is given IV or orally every 6 hours for 7 treatments.

N- acetylcysteine is most effective when initiated early in treatment but can still be somewhat helpful 36- 80 hours after ingestion. In humans hepatic toxicity is prevented when N-acetylcysteine is administered within 8 hours of exposure but as time increases after ingestion hepatic necrosis occurs (but is reduced).

N- acetylcysteine may reduce methemoglobin formation in erythrocytes by increasing production of glutathione and favoring production of nontoxic instead of reactive intermediates. It may also act to reduce intermediate free radicals.

Cimetidine inhibits cytochrome P-450 and has been suggested for the treatment of acetaminophen. It would have to be given very early after ingestion and even with high doses complete inhibition of cytochrome P-450 does not occur. Cimetidine must be used as an adjunct to therapy; the dose is 5 mg/kg IV every 8 hours.

Vitamin C is an antioxidant and has been used in the treatment of acetaminophen toxicity. It can alleviate methemoglobinemia and supplement glutathione to prevent covalent bonding of reactive metabolites. The recommended dose is 30 g/kg IV every 6 hours.

Blood transfusions can be given for anemia but the guidelines for transfusions are different than for treatment of other anemias. The hematocrit of the patient is not a reflection of oxygen-carrying capacity in the presence of methemoglobinemia. Rather, the patient is monitored for signs of hypoxemia and treated accordingly.

Treatment of coagulapathies is complex and is briefly mentioned in the following summary of treatments. Readers are directed to other sources for information: (Speeg KV, Bay MK: Prevention and treatment of drug-induced liver disease. Gastroenterol Clin North Am 24:1047-1064,1995 and Plumb DC; Veterinary Drug Book. Ames, Iowa, Iowa State University Press, 1995).

Prophylactic antibiotics (cefazolin or ampicillin at 20 mg/kg IV every 8 hours) are administered to protect the patient from infection from secondary gastrointestinal translocation. This is because the liver has a reduced capacity to clear this bacteria.

Liver necrosis leads to impaired gluconeogenesis, prolonged insulin half-life and impaired mobilization of glycogen stores - therefore intravenous dextrose solutions are necessary.

Lactulose (1-3 ml/kg PO or via enema every 4 to 6 hours), can be used to help treat hepatoencephalopathy.

Future Therapies

In one study in rats dietary supplementation of glutamine helped replenish glutathione stores after toxic ingestions.

Prostaglandin E2 is believed to be cytoprotective and in a study comparing prostaglandin with N-acetylcysteine, serum alanine aminotransferase levels were near normal in the prostaglandin group 24 hours post-ingestion but were still 9 times higher in the N-acetylcysteine group. Histopathological hepatic injury was also reduced in the prostaglandin group.


The toxic effects of acetaminophen are related to formation of NAPQI via cytochrome P-450 after sulfate and glucuronide pathways are saturated and glutathione stores are depleted. Liver and erythrocyte damage occurs with glutathione depletion and liver necrosis and methemoglobinemia occur. Toxicity is dose dependent. Cats can show signs with as little as 10 mg/kg while 150 to 200 mg/kg is considered toxic in dogs.

Clinical signs are similar in dogs and cats but in dogs liver necrosis is more prevalent than in cats, in which methemoglobinemia and Heinz-Body formation more commonly occur.

N-acetylcysteine is essential for treatment because it provides cysteine for synthesis of glutathione and also reacts with NAPQI to produce nontoxic conjugates. Cimetidine and vitamin C are also helpful, along with intravenous fluids, supplemental oxygen, treatment of liver disease and blood products (if indicated).

Treatment Protocol of Acetaminophen Toxicosis

1. Supplemental oxygen
2. Minimize stress and handling
3. Intravenous fluids: sufficient to maintain mean arterial pressure above 80 mm Hg and promote diuresis
4. N- acetylcysteine:
loading of 140 mg/kg IV
then 70 mg/kg IV or PO q 6 hours for 7 treatments
5. Cimetidine at 5 mg/kg IV TID
6. Vitamin C at 30 g/kg IV QID
7. If in liver failure:
Lactulose: 1-3 ml/kg PO q 4-6 hours
Neomycin/Metronidazole: Neomycin: 15 mg/kg as enema QID or 10-20 mg/kg PO QID ; Metronidazole: 20 mg/kg PO TID or 10 mg/kg IV TID
8. Treat coagulopathies as necessary:
Fresh Frozen Plasma: 10 ml/kg IV
Glucose: 0.5 -1.0 ml/kg 50% dextrose IV as necessary to maintain glucose above 40 mg/dl then 2.5% to 5% dextrose added to fluids
Vitamin K: 2-4 mg/kg SQ BID to TID
Blood products: as needed
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