Acetaminophen

Chapter 28 Acetaminophen



Rance K. Sellon, DVM, PhD





• Expected single toxic doses of acetaminophen range from 600 mg/kg (dogs) to 50 to 100 mg/kg (cats). Toxicity may be observed with lower doses, particularly with chronic exposure.

• Clinical signs of toxicity usually reflect hepatic injury or failure (dogs) and hemolytic anemia from methemoglobinemia (cats).

• Diagnosis is typically made from a history of exposure coupled with compatible clinical and laboratory findings.

• The mainstay of therapy is administration of N-acetylcysteine at a loading dose of 140 mg/kg IV or PO every 6 hours, followed by 70 mg/kg IV or PO every 6 hours for five to seven or more doses. SAMe may also be therapeutic for intoxicated animals.

• Supportive treatment measures, such as IV fluids and blood, are necessary in many cases.


SOURCES


Acetaminophen is a widely available analgesic and antipyretic contained in many over-the-counter preparations intended for human use. Exposure to dogs and cats occurs through administration of one of these preparations by an uninformed but well-meaning owner intending to treat fever or pain perceived in the pet or by accidental ingestion of a toxic dose. Accidental ingestion of a toxic dose has been the most common cause of toxicosis in dogs.1 Acetaminophen may also be generated from the metabolism of phenacetin, an ingredient of some analgesic mixtures. In Australia and Great Britain, paracetamol is the equivalent of acetaminophen.



TOXIC DOSE



Dogs


The recommended therapeutic dosage of acetaminophen in dogs is 15 mg/kg given orally every 8 hours. The reported dose required to produce signs of toxicity in dogs is approximately 600 mg/kg, although clinical signs of toxicity have been seen in dogs at doses in the range of 200 mg/kg.2 Clinical signs of toxicity have been observed in occasional dogs at much lower doses. In one published report, a dog with hematological evidence of acetaminophen toxicosis was administered roughly 46 mg/kg daily for 6 weeks.3 The author is aware of cases of clinical toxicosis in dogs following chronic administration of therapeutic doses.



Cats


Compared with dogs, cats are extremely sensitive to the toxic effects of acetaminophen and can have clinical signs of toxicity with doses in the range of 50 to 100 mg/kg. Toxicosis has been occasionally observed with doses as low as 10 mg/kg.4 In cats that have received subtoxic doses of acetaminophen, subsequent doses can prove rapidly fatal.



TOXICOKINETICS


Because of product formulations, most acetaminophen poisonings that develop in dogs and cats follow oral ingestion. After ingestion the drug is rapidly absorbed into the portal circulation and metabolized in the liver by glucuronidation, sulfation, and cytochrome P450-mediated pathways. In dogs, as in many other species, low doses of acetaminophen are metabolized primarily through the glucuronidation and sulfation pathways, with the resulting nontoxic conjugates excreted in bile and urine.5


Although the amount of acetaminophen metabolized through the cytochrome P450 pathway is usually small, the product of this metabolic pathway, N-acetyl benzoquinoneimine, is toxic. The toxic effects of N-acetyl benzoquinoneimine are normally limited by its conjugation with glutathione, a compound essential for cellular protection against oxidative injury, to form nontoxic cysteine and mercapturic acid conjugates. Because the metabolism of acetaminophen by glucuronidation and sulfation pathways is capacity limited, increasing doses of acetaminophen lead to an increased proportion of the drug that is metabolized by the cytochrome P450 system and an increase in the production of N-acetyl benzoquinoneimine. Cellular stores of glutathione become depleted during conjugation of the increased amounts of N-acetyl benzoquinoneimine. In addition, synthesis of glutathione is suppressed in the face of high concentrations of acetaminophen. The end result is increased concentrations of unconjugated N-acetyl benzoquinoneimine. In dogs the biotransformation of acetaminophen is also a dose-dependent event: the higher the dose, the longer it takes for the biotransformation process to occur.2


Cats, like dogs, also exhibit dose-dependent toxicokinetics, albeit with some important differences.2 Relative to a number of other species, cats have low hepatic levels of high-affinity acetaminophen uridine diphosphate (UDP)-glucuronosyltransferase (acetaminophen-uridine diphosphate glucuronosyltransferase [UGT]).6 Compared with dogs therefore, cats have a diminished capacity to metabolize acetaminophen through the glucuronidation pathway, and more of the drug is transformed through the sulfation pathway. As in dogs, the sulfation pathway of cats is also capacity limited. Additionally, the dose dependency of biotransformation in cats occurs at doses approximately one tenth those observed for dogs. A capacity-limited sulfation pathway, poor glucuronidation capacity, and lower threshold for dose-dependent biotransformation explain the sensitivity of cats to acetaminophen toxicity, which occurs at much lower doses than in dogs.



MECHANISM OF TOXICITY


Central to the mechanism of acetaminophen poisoning in dogs and cats is depletion of cellular glutathione. In the absence of glutathione conjugation, increased concentrations of N-acetyl benzoquinoneimine accumulate. Because of its electrophilic properties, N-acetyl benzoquinoneimine covalently binds to cellular proteins (e.g., enzymes, structural and regulatory proteins), thereby disrupting protein function and damaging cellular membranes through lipid peroxidation. Additionally, glutathione depletion renders cells susceptible to oxidative injury. In dogs the liver is more susceptible to the toxicity of acetaminophen, whereas in cats the red blood cell is most susceptible to oxidative injury following glutathione depletion. The reasons for the differences in tissue affected are believed to lie in the comparative susceptibility of red blood cells to oxidative injury. Feline hemoglobin contains eight sulfhydryl groups, compared with four sulfhydryl groups in other species. Feline erythrocytes are thus much more prone to oxidative injury, making the development of methemoglobinemia a much earlier and more prominent feature of toxicosis in cats than in dogs.



CLINICAL SIGNS



Dogs


In dogs the clinical signs of acetaminophen toxicosis most commonly reflect hepatocellular injury and necrosis. At higher toxic doses, clinical signs of methemoglobinemia may become apparent. It is possible for an occasional dog to exhibit signs more referable to methemoglobinemia than to hepatotoxicity.7,8 Vomiting, anorexia, tachycardia, and tachypnea are most often described. There may be abdominal pain and icterus. If methemoglobinemia is present, cyanosis, hemoglobinuria, and hematuria may also be observed. Facial and paw edema are commonly reported.



Cats


Clinical signs of acetaminophen toxicosis in cats are similar to those for dogs except that cats do not develop hepatotoxicosis as readily. The most common clinical signs reported include cyanosis or muddy mucous membranes, respiratory distress, edema of the face and paws, depression, hypothermia, and vomiting. Icterus may also develop, most commonly as a consequence of hemolysis. Signs associated with hepatotoxicosis in cats are more commonly seen in high-dose exposures and in males.

Related posts:

  1. Miscellaneous Indoor Toxicants
  2. Considerations in Pregnant or Lactating Patients
  3. Cyanide
  4. Grapes and Raisins

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Sep 11, 2016 | Posted by in SMALL ANIMAL | Comments Off on Acetaminophen

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