Acetaminophen

Chapter 79 Acetaminophen



Amy J. Alwood, DVM



KEY POINTS



• Acetaminophen toxicity from accidental exposure or deliberate administration in dogs and cats is the second most common cause of nonsteroidal antiinflammatory drug (NSAID) toxicity in small animals.

• Acetaminophen toxicity may result from dosages exceeding 75 mg/kg in the dog, although dosages as low as 10 mg/kg have been associated with toxicity in the cat.

• Toxicity from acetaminophen results when the metabolic pathways for glucuronidation and sulfation are absent or depleted and the toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) accumulates, causing oxidative injury.

• The principal management for acetaminophen toxicity is the administration of acetylcysteine, although other adjunctive therapies have been described.


INTRODUCTION


Acetaminophen is an analgesic and antipyretic that is derived from the chemical compound paracetamol (para-amino-phenol). Although acetaminophen is a common and safe over-the-counter analgesic for people, a narrow margin of safety in dogs and cats limits its use in small animal patients. However, these same drug characteristics, and the presence of acetaminophen in most American households, make cases of toxic exposure commonplace for the small animal veterinarian. The American Society for the Prevention of Cruelty to Animals Animal Poison Control Center reported over 1000 cases of accidental acetaminophen exposure from 1998 to 2000.1 Acetaminophen represents the second most common cause of nonsteroidal antiinflammatory drug (NSAID) toxicity in dogs and cats.1,2



THERAPEUTIC USE OF ACETAMINOPHEN


Acetaminophen is an analgesic which is commonly used in the management of mild to moderate pain when an opioid is not needed and another NSAID is not desired or is contraindicated. The mechanism of analgesia provided by acetaminophen is not well understood but involves an increase of the pain threshold and possible inhibition of cyclooxygenase.3 Antipyretic effects of the drug are centrally mediated at the level of the hypothalamus.3 Acetaminophen is a weak prostaglandin inhibitor and therefore has no significant antiinflammatory effects. It is not known to alter platelet function.3



Preparations and Routes of Administration


Acetaminophen is available over the counter and by prescription. Oral tablets, liquid preparations, and suppositories are available.3,4 Acetaminophen is also available in combination with other drugs including opioids, antihistamines, and decongestants. Over 200 prescription and over-the-counter formulations are available, including more than 30 combination preparations.1,4 Acetaminophen has been used safely in appropriate dosages in dogs. The recommended dosage is 10 to 15 mg/kg PO q 6-12 hr.1,5 However, concerns about toxicity with inappropriate administration and the availability of alternative analgesics limit the use of acetaminophen in dogs. Acetaminophen is not recommended for therapeutic use in cats because of the unique risk of toxicity in this species.



PHARMACOLOGY AND PHARMACOKINETICS


Acetaminophen is absorbed rapidly after oral administration.3-6 Peak blood concentrations typically are reached within 30 to 60 minutes.5 After absorption, acetaminophen undergoes partial metabolism in the liver by microsomal enzymes. At least 90% of the drug is ultimately metabolized to the nontoxic conjugates (sulfate and glucuronide). A small amount of drug (approximately 5%) is excreted unchanged in the urine. Another 5% of drug is metabolized to a nontherapeutic metabolite (i.e., NAPQI) which becomes important with excessive ingestion.1,5-8 The half-life of acetaminophen is normally between 0.6 and 3 hours, but may be prolonged in animals with toxic levels of exposure or hepatic disease.5,6,8 In the dog, glucuronide predominates as the major metabolite excreted in the urine, although sulfate metabolites predominate in the cat.8 With therapeutic dosing, increased hepatic enzymes may be noted, and with long-term therapy, hepatic injury or failure may occur.3-5



PATHOPHYSIOLOGY OF TOXIC EXPOSURE


Toxicity from acetaminophen occurs when critical metabolic pathways are either absent, deficient, or saturated.1,6-8 NAPQI is a highly active metabolite that alters the chemical structure of proteins and lipids and causes cellular damage.1,6 NAPQI can be neutralized by binding with the sulfhydryl groups of endogenous glutathione.1,6 When glutathione supplies are limited (as in the cat) or depleted (as with toxic exposure in any species), NAPQI accumulates and causes injury. NAPQI is a reactive oxygen species (free radical) that causes injury by binding cellular macromolecules, causing lipid peroxidation of membranes, and inducing direct cell injury and death.6 In patients with hepatic dysfunction (chronic liver disease) or increased activity of the cytochrome P450 enzyme system (drug-mediated enzyme induction such as with anticonvulsant therapy), toxicity may be more severe or may occur with lower levels of drug exposure.6 Primary or secondary damage may occur in the liver, red blood cells, kidneys, central nervous system (CNS), and gastrointestinal (GI) tract. Further details and mechanisms of injury are summarized in Table 79-1.


Table 79-1 Mechanisms of Acetaminophen-Induced Injury by Organ System6,8



























Organ System Mechanism of Injury Site of Injury
Hepatic Binding of NAPQI to sulfhydryl groups within the hepatocytes Hepatocellular death and central lobular necrosis as NAPQI covalently binds to vital proteins and the lipid bilayer of hepatocyte membranes
Location believed to be a result of the higher concentrations of cytochrome P450 around the central vein
Hematologic Binding of NAPQI and associated oxidative injury to the erythrocyte membrane and hemoglobin molecules Methemoglobinemia, Heinz body formation, and associated hemolytic anemia
Thrombocytopenia has also been reported with toxicities in humans
Renal Primary renal injury is less common; however, when it does occur the mechanism of injury is likely similar to that associated with direct hepatic injury (cytochrome P450 present in the proximal renal tubules) Either direct acute renal tubular necrosis, or
secondary renal injury via hepatorenal syndrome
Central nervous system Mechanism of primary injury not well described Hepatic encephalopathy secondary to hepatic injury
Primary neurologic injury may be uncommon
Coma reported in some cases of human and feline toxicity
Gastrointestinal Secondary involvement a consequence of hepatotoxicity
Primary gastrointestinal injury uncommon		 Gastritis, gastric ulceration, gastric necrosis

NAPQI,N-Acetyl-p-benzoquinone-imine.

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Acetaminophen

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