Acetaminophen Toxicity

• Acetaminophen (N-acetyl-p-aminophenol) is a widely used OTC and prescription drug with antipyretic and analgesic effects, better known as “Tylenol,” APAP or paracetamol.
• Acetaminophen has no anti-inflammatory properties and is not classed as an NSAID.
• Accidental toxicosis occurs in dogs, cats and ferrets — either through the pet getting into the medication or through well-meaning owners who do not know its toxic dose or safety profile.
• Clinical toxicosis appears in dogs at >100–150 mg/kg, whereas cats and ferrets can be poisoned at 10–50 mg/kg.
• Toxicosis causes methemoglobinemia (cats, less commonly dogs) or hepatotoxicity (dogs, less commonly cats).
• Typical signs are malaise, anorexia, swelling of the paws or face, vomiting, respiratory distress, brown mucous membranes and icterus.
• Unlike most toxicants, acetaminophen has an antidote — N-acetylcysteine (NAC) — so with supportive care the prognosis is fair to excellent.

• Acetaminophen is a COX-3 inhibitor.
• Acetaminophen is cleared by two routes. Most is conjugated to inactive glucuronide and sulfate metabolites; the rest is converted by the cytochrome P450 system into the toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI). When the glucuronidation and sulfation pathways are exhausted, the toxic metabolite builds up and causes oxidative injury to red blood cells and hepatic proteins.
• Acetaminophen is absorbed quickly from the stomach and GIT, and peak blood levels are reached within 30–60 minutes.

• Gastrointestinal: mild, nonspecific GI signs early on; more severe signs once hepatic failure advances.
• Skin/exocrine: facial or paw swelling in both cats and dogs by an unknown mechanism; icterus with hepatotoxicity.
• Hemic/lymphatic/immune: glutathione depletion leads to oxidative injury of RBCs and Hb, causing MetHb and Heinz body anemia.
• Respiratory: respiratory distress because MetHb cannot carry oxygen.
• Cardiovascular: shock secondary to anemic hypoxia.
• Hepatobiliary: hepatocellular injury and hepatic necrosis caused by NAPQI.
• Nervous: hepatic encephalopathy secondary to hepatotoxicity.
• Ophthalmic: KCS has been reported in dogs given acetaminophen, even at subtoxic doses.
• Renal/urologic: very large doses can rarely cause renal tubular necrosis, reported so far only in humans.

• Dogs, cats and ferrets.
• Cats are the most sensitive: their limited glucuronide conjugation lets toxic NAPQI build up at far lower doses than in dogs.
• Ferrets share the cat’s low toxic threshold (10–50 mg/kg).

• None reported; risk depends on the species and on access to medication in the household, not on breed.

• Acetaminophen overdose

• Evidence of a tampered or chewed container or prescription bottle.
• Owner administration.
• Clinical signs consistent with acetaminophen toxicosis

• When liver enzymes are raised or a hepatopathy is suspected, rule out other hepatotoxicants (e.g., sago palm, Amanita mushrooms, xylitol, blue-green algae, aflatoxins), metabolic causes (e.g., cholangiohepatitis, extrahepatic bile duct obstruction, pancreatitis), neoplasia, and infectious causes (e.g., Leptospira).
• When the patient presents with anemia, also consider other toxicants (zinc, mothballs such as naphthalene, Allium spp. such as onions and garlic, local anesthetics such as benzocaine), metabolic causes (e.g., IMHA), infectious causes (e.g., Mycoplasma felis) and neoplasia.

• Heinz bodies, especially in cats
• Possibly anemia due to lysis of affected red blood cells
• Elevated ALT, Alk Phos
• Liver values may increase 24 to 36 hours post-ingestion.
• Elevated total and direct bilirubin
• Serum may be icteric
• Large doses may be nephrotoxic; may see increases in BUN and creatinine
• May see orange or dark colored urine with hemoglobinuria or methemoglobinuria

• Arterial blood gas
• Methemoglobinemia is suspected when dark-colored blood has a normal or high PaO₂.
• May show a metabolic acidosis
• Schirmer tear test
• An idiosyncratic reaction has been shown to cause KCS
• Sometimes seen at doses below the toxic dose
• Smaller dogs may be more susceptible
• Acetaminophen serum levels
• Can be measured at many human hospitals
• Highest level occurs 1 to 3 hours after ingestion
• Estimate metHb
• Place a drop of blood on white filter paper; it looks brown if metHb is > 15 percent.
• Normal <1 percent
• 20 to 40 percent metHb causes respiratory difficulty
• 40 to 55 percent metHb causes neurologic depression
• 70 percent metHb is acutely life-threatening

• Drugs that may perpetuate clinical signs

• Drugs metabolized by the liver may have prolonged half-lives, and drugs that need hepatic biotransformation may be less effective.

• Activity should be restricted.

• Evaluate immediately when presented with brown or cyanotic mucous membranes.

• Handle clinically affected animals gently and keep stress to a minimum, especially in cats.
• Animals presenting in respiratory distress may need immediate oxygen supplementation.

• Clients should know that treating severe cases can be prolonged and expensive.
• Affected animals may be left with residual liver damage.

• Monitor liver enzymes every 12 to 24 hours initially.

• Drugs that are metabolized by the liver may have prolonged half-lives.
• Never give acetaminophen to cats.
• Be very cautious when giving acetaminophen to dogs.

• Liver necrosis and fibrosis
• Death

• Clinical signs may last 12 to 48 hours.
• Rising liver enzymes 12 to 48 hours after ingestion are a serious concern.
• Cats may die of methemoglobinemia up to 36 hours after ingestion.
• Dogs may die of liver failure several days after ingestion.
• Animals treated promptly can be expected to recover completely.
• Once clinical signs appear, the prognosis is guarded to poor in cats and better in dogs.

• Tylenol
• Paracetamol

• ALT : alanine aminotransferase
• Alk Phos : alkaline phosphatase
• BUN : blood urea nitrogen
• IM : intramuscularly
• IV : intravenously
• KCS : keratoconjunctivitis sicca
• metHb : methemoglobin
• NAPQI : N-acetyl-para-benzoquinoneimine
• NSAIDs : nonsteroidal anti-inflammatory drugs
• PaO₂ : partial pressure of oxygen in arterial blood
• PO : by mouth
• SQ : subcutaneously

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Wallace KP, Center SA, Hickford FH. S-adenosyl-L-methionine (SAMe) for the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc 2002; 38:246–254.

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