Acetaminophen Toxicosis Flashcards
What is the main source of Acetaminophen? Is it commonly used in dogs and cats?
analgesic and antipyretic derivatives of N-acetyl-p-aminophenol present in many OTC formulations
NO - has a low safety margin
- most common drug toxicosis in cats
What are the most common causes of Acetaminophen toxicosis? In what animals is use contraindicated?
ORAL EXPOSURE
- well-meaning, but ill-informed administration to cats by owners
- accidental ingestion of owner’s medications, especially in dogs
cats and ferrets
How is the elimination half-life of Acetaminophen affected by dose in cats?
increased dose = increased elimination half-life
What are the main 3 pathways of Acetaminophen metabolism in the liver?
- glucuronidation - dose-dependent, LOW IN CATS
- sulfation - dose-dependent in dogs and cats (main pathway in cats)
- cytochrome P450 - metabolizes into N-acetyl-p-benzoquinoneimine (NAPQI), which is a toxic electrophile that is conjugated by reduced glutathione (GSH)
What pathways of Acetaminophen metabolism are capacity limited? What does this mean?
glucuronidation and sulfation - higher the dose = longer it take for the biotransformation process to occur
How is Acetaminophen deacetylated in the liver? Why does this pathway lead to toxicosis in cats and dogs?
carboxylesterases deacetylate into p-aminophenol (PAP), which is able to cause oxidative damage to RBCs resulting in methemoglobinemia
cats and dogs are deficient in N-acetyltransferase, which usually converts PAP back into acetaminophen, which leads to a buildup of PAP and methemoglobinemia
Acetaminophen metabolism:
When does Acetaminophen toxicity occur?
when conjugation pathways and GSH scavenging capacity are exceeded, resulting in accumulation of NAPQI
What are the 3 mechanisms of toxicity of NAPQI in Acetaminophen toxicosis?
- depletes GSH and decreases GSH production, which increases susceptibility to oxidative stress
- covalently binds to sulfhydryl-containing proteins, especially in the mitochondria, decreasing ATP and causing cell death (primarily in the liver)
- targets plasma membrane proteins and calcium homeostasis
How do NAPQI and Acetaminophen affect RBCs? What injuries predominate in dogs and cats?
oxidizes hemoglobin into methemoglobin, forming Heinz bodies which increase the fragility and decrease the survival time of RBCs —> hemolytic anemia and cyanosis
- DOGS: oxidative hepatic damage
- CATS: erythrocyte injury
What are the 2 confounding factors increase Acetaminophen toxicity? What 2 decrease?
- fasting/starvation depletes GSH
- barbiturates induce CYP450, which increases NAPQI formation
- Cimetidine inhibits CYP450, which decreases NAPQI formation
- young animals are more resistant due to the immaturity of their enzyme systems and rapid GSH synthesis
What 4 things make cats more susceptible to Acetaminophen toxicosis?
- low threshold for dose-dependent biotransformation due to their deficiency in glucuronidation and capacity of their sulfation pathway is low
- feline hemoglobin is more susceptible oxidation
- lower levels of methemoglobin reductase
- propylene glycol has been used in wet food and contributes to increased sensitivity of feline RBC and the formation of Heinz bodies
Why are cats deficient in glucuronidation? How does their sulfation pathway compare to dogs?
low levels of uridine diphosphate glucuronosyltransferase
dose-dependency of biotransformation occurs at lower doses in cats compared to dogs
Why are cats’ hemoglobin more susceptible to oxidation?
has 8 reactive sulfhydryl groups per hemoglobin compared to 4 in dogs and 2 in humans
What clinical signs are most common in dogs with Acetaminophen toxicity? What occurs at higher doses? What else is commonly reported?
hepatic injury with centrilobular necrosis - nausea, vomiting, abdominal pain, depression, anorexia, chemosis, shock, elevated liver enzymes (ALT, AST), icterus
methemoglobinemia - hemoglobinuria, hematuria, anemia, hemolysis, cyanosis, lethargy, tachypnea, recumbency
facial and paw edema
What likely causes facial and paw edema in Acetaminophen toxicity?
vascular endothelial damage
