Paracetamol intoxication

Question 1

What is the mechanism of toxicity of paracetamol

Answer 1

Paracetamol is rapidly absorbed from the GI tract and widely distributed throughout the body

It is not the paracetamol itself that is responsible for the toxic effects but its metabolite NAPQI (N-Acetyl-p-benzoquinone imine)
- after absorption of paracetamol, the majority (90%) is excreted as non-toxic metabolites following glucuronidation and sulfation
- as cats have low level of the enzyme glucuronyl transferase, the glucuronidation pathway is soon saturated and any remaining paracetamol is processed within the P450 system, producing the toxic NAPQI
- as a free radical, NAPQI can lead to substantial oxidative cell damage

Question 2

Explain why cats are particularly susceptible to red cell oxidative damage

Answer 2

Cats are particularly susceptible to red cell oxidative damage because:
- they have eight sulfudryl groups per hemoglobin tetramer compared with the four found in fumans and dogs
- additionally, the different structural anatomy of the feline spleen is partially responsible for a decreased ability to recognise and remove red blood cells with Heinz bodies, thus increasing the circulation time of these dysfunctional cells

Question 3

What are the clinical signs of paracetamol intoxication

Answer 3

Depression, anorexia, hypersalivation, vomiting may occur after ingestion of as little as 10 mg/kg paracetamol

Between 24 and 72 h, some cats develop facial edema, with the paws and forelimbs occasionally being affected

Patients develop methemoglobinuria and signs associated with hemolysis/methemoglobinemia:
- tachypnoea
- chocolate-colored or icteric mucous membranes
- abdominal pain

Question 4

What would be your treatment plan for paracetamol intoxication

Answer 4

If ingestion occured over an hour before presentation, induction of emesis might be ineffective

Administartion of activated charcoal is usually valuable as it absorbs paracetamol efficiently

Agressive supportive care to ensure tissue oxygen delivery is the cornerstone of stabilisation
- oxygen
- blood transfusion

Several specific treatments may also be instituted to reduce oxidative damage
- N-acetylcysteine (=additional source of glutathione)
- loading dose of 140 mg/kg, PO or IV, followed by 70 mg/kg, PO or IV, q 4h for five to seven treatments
- oral administration can be challenging due to its bitter taste
- S-adenosylmethionine has been shown to protect cat erythrocytes from oxidative injury
- dose: 180 mg, PO, q 12h for 3 days then 90 mg, PO, q 12 h for 14 days

Question 5

Explain why cats are more susceptible to paracetamol toxicity than dogs

Answer 5

Glucuronidation and sulfation are the two major conjugation pathways used by most species to metabolize paracetamol
- unfortunately, cats are deficient in glucuronyl transferase and are poor sulfators so cats cannot metabolize paracetamol to its nontoxic metabolites
- paracetamol is metabolized through the P450 system resulting in the oxidative metabolite N-acetyl-para-benzoquinoneimin (NAPQI)

Question 6

Which metabolite of paracetamol seems to be responsible for methemoglobinemia in cats

Answer 6

Para-aminophenol is a reactive compound that can co-oxidate with hemoglobin to form methemoglobin

Para-aminophenol accumulates in RBCs and appear to be the metabolite responsible for methemoglobinemia and Heinz body formation

Cats are deficient in arylamine NAT activity which contributes to this species-dependent methemoglobinemia

Cats also have a relative deficiency of methemoglobin reductase in their RBCs