Acetaminophen toxicity

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Acetaminophen (paracetamol) toxicity is a common cause of sudden death due to methemoglobinemia, hemolysis and acute liver necrosis in dogs[1].

The toxic dose of acetaminophen is > 200 mg/kg in dogs[2].

In dogs, acetaminophen undergoes both toxic and nontoxic biotransformation in the liver, resulting in production of a byproduct para-aminophenol in the liver, which induces methemoglobinemia. This is a species specific anomaly in dogs and cats due to a deficiency in hepatic arylamine N-acetyltransferase activity[3].

Acetaminophen is conjugated with glucuronide and sulfate by transferase enzymes but only a small portion of a dose is converted to reactive metabolites by the cytochrome P-450-dependent mixed function oxidase system[4]. The reactive metabolites formed may subsequently become conjugated with glutathione and excreted in the urine as nontoxic metabolites[5]. Toxicity results if the active metabolite depletes glutathione stores[6].

Affected dogs invariably have a history of acetaminophen ingestion and following a brief interlude present with whole body tremors, weakness, tachypnea, tachycardia and stupor may be evident.

Mucous membranes are usually bluish and cyanotic and the tongue is often a grey-blue color. In rare cases, icterus has been noted following a single ingestion[7]. Edema of the face and paws is frequently observed[8].

Diagnosis is based on presenting clinical signs together with blood samples which usually show evidence of dark brown-colored blood, hypoalbuminemia, elevated ALT and AST, and Heinz-body anemia[9]. Urinalysis may reveal hemoglobinuria[10].

A differential diagnosis would include congenital methemoglobinemia, phosphofructokinase deficiency, pyruvate kinase deficiency and glucose-6-phosphate deficiency.

Supportive intravenous fluids and oxygen therapy are usually given to effect, and N-acetylcysteine is considered an antidote for this toxin, given at 140 mg/kg over a 6 - 8 hour interval.

Treatment with s-adenosyl-l-methionine as a glutathione donor has also showed promise when given at a loading dose of 40 mg/kg body weight orally, followed by a maintenance dose of 20 mg/kg once dailt for 7 days[11].

The use of sodium bicarbonate, ascorbic acid and S-adenosylmethionine may also help minimize the oxidative effects of acetaminophen.

References

  1. Taylor NS & Dhupa N (2000) Acetaminophen toxicity in cats and dogs. Compend Contin Educ Pract Vet 22(2):160–169
  2. Villar D & Buck WB (1998) Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats. Vet Hum Toxicol 40:156–162
  3. McConkey SE et al (2009) The role of para-aminophenol in acetaminophen-induced methemoglobinemia in dogs and cats. J Vet Pharmacol Ther 32(6):585-595
  4. Savides MC et al (1984) The toxicity and biotransformation of single doses of acetaminophen in dogs and cats. Toxicol Appl Pharmacol 74:26–34
  5. Nash SL & Oehme FW (1984) A review of acetaminophen's effect on methemoglobin, glutathione, and some related enzymes. Vet Hum Toxicol 26:123–132
  6. Hjelle JJ & Grauer GF (1986) Acetaminophen-induced toxicosis in dogs and cats. J Am Vet Med Assoc 188:742-746
  7. Schlesinger DP (1995) Methemoglobinemia and anemia in a dog with acetaminophen toxicity. Can Vet J 36(8):515-517
  8. Plunkett SJ (2000) Emergency Procedures for the Small Animal Veterinarian, ed 2. London, WB Saunders. pp:279–281
  9. Gfeller RW & Messonnier SP (2004) Handbook of Small Animal Toxicology and Poisonings, ed 2. St. Louis, Mosby. pp:68–73
  10. MacNaughton SM (2003) Acetaminophen toxicosis in a Dalmatian. Can Vet J 44(2):142-144
  11. Wallace KP et al (2002) S-adenosyl-L-methionine (SAMe) for the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc 38(3):246-254