Acetaminophen toxicosis

From Felipedia

Acetaminophen is an NSAID class of drug (nonsteroidal anti-inflammatory) commonly used in humans, and often accidentally, for pain relief in cats. Unfortunately, like aspirin, acetaminophen is a toxin to cats, even at small dosese.

Mechanism of action

Phenacetin is metabolized to acetaminophen. Acetaminophen is metabolized by enzymes of the cytochrome P-450 series to intermediate products: nonreactive glucuronides and sulfates (which are conjugated and eliminated in the urine), and reactive metabolites, which are metabolized with glutathione to nontoxic mercapturic acid (which is eliminated). If the toxic metabolites accumulate as a result of insufficient glucuronide or sulfate metabolism or insufficient glutathione, they are converted to toxic macromolecules that directly cause cellular death. Cats lack glucuronyl transferase and inefficiently form glucuronic acid and sulfate conjugates, leaving more acetaminophen or phenacetin to be metabolized to toxic metabolites. The glutathione stores are rapidly depleted in cats, leaving a large amount of toxic metabolites. Methemoglobinernia occurs.

Clinical signs

Toxicosis usually occurs when well-intentioned owners, unaware of the significant toxicity of this drug in cats, administer the drug for a variety of reasons. Ingestion of 50-60 mg/kg of acetaminophen may be fatal for cats. This amounts to one regular-strength tablet for a 4-5 kg cat. Acetaminophen preys on several of the cat's metabolic peculiarities and leads to the development of life-threatening methemoglobinemia and Heinz-body anaemia.

Acute signs in cats are related to methemoglobin formation, whereas acute signs in the dog are related to hepatic damage. Toxicity is mainly seen in cats when even a small amount of acetarninophen is ingested (half of a 325 mg tablet for a 3.5 kg cat); dogs can usually tolerate dosages up to 100 mg/kg. Signs include cyanosis (which is caused by methemoglobinemia), dyspnea, facial edema (a hallmark of acetaminophen poisoning mechanism unknown), depression, hypothermia, vomiting. Signs may progress to weakness, coma, and subsequently death. Increased ALT from hepatic damage may be seen.

Treatment

Since the toxic metabolites bind preferentially with glutathione rather than cell macromolecules, supplying a glutathione precursor is an important part of treatment. N-Acetylcysteine provides the cysteine needed for glutathione synthesis and also increases serum sulfate levels, which supplies sulfate for conjugation. Ascorbic acid is used to change methemoglobin to reduced hemoglobin. Acetaminophen is rapidly absorbed and reaches peak blood levels within 30 to 60 minutes; emesis is performed immediately after ingestion (if possible), and a saline cathartic is given. Steroids should not be given because they have been reported to cause a dose-dependent increase in mortality. Antihistamines have been reported to be contraindicated.