Acetaminophen Toxicity

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Pharmacokinetics of acetaminophen: upon ingestion, acetaminophen is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved in 30-60 minutes. Food may delay the time to the achieving peak concentration but the extent of absorption is not affected. With overdoses, peak plasma levels are reached within 4 hours. Half life of this drug is mostly 2-3 hours, but could increase upto 4 hours in hepatic injury. 

Metabolismthis drug is extensively metabolized through liver via 3 hepatic pathways. 

a) 1st is through glucuronidation and sulfation.  About 90% of drug gets conjugated to sulfated and glucuronidated metabolites, and  is then really excreted.

b) Rest of the 2% gets excreted in urine in an unchanged form.

c) and the remaining undergoes CYP450 mediated oxidation. This results in the production of an active metabolite, N – acetyl- p– benzoquinone imine(NAPQI). In normal conditions, when there is no overdosing of this drug, the active metabolite reacts with the sulfhydryl groups in glutathione,  and converts the metabolite into a harmless metabolite before being excreted in urine.

Recommended dose: In adults, it is 650-1000 mg every 4-6 hours. Not to exceed 3250mg  in a 24 hours period. Single doses of more than 150mg/kg or 7.5g in adults is considered potentially toxic, but liver injury can occur at minimal amounts. In children, 10-15mg/kg every 4-6 hours is recommended and use of 50-70mg/kg in 24 hours period. In children single doses of 120mg/kg – 150mg/kg are thought to be associated with hepatotoxicity. 

Acetaminophen Toxicity: it could either be a result of large acute dosing, i.e. consuming amounts of drug more than the specified safe limits, i.e. in toxic amounts in a single time, or could be  due to the chronic use of the drug, meaning repeated doses, or above the recommended limits.

With large acute doses or with chronic use,  the major metabolic pathways, glucuronide and sulfate conjugation systems become saturated and more drug is subjected to be metabolized through CYP450 system. This leads to an increased production of NAPQI. More and more NAPQI binds to glutathione and when approximately 70% of glutathione is depleted, the active metabolite NAPQI begins to accumulate in the hepatocytes, resulting in the hepatic damage.

Clinical presentation of acetaminophen toxicity: it is presented in 4 phases.

Phase 1: preclinical toxic effects.  This phase occurs a few hours after the ingestion of a toxic dose and lasts for 12-24 hours. Symptoms during first 24 hours are not diagnostic and usually includes nausea,  vomiting,  diaphoresis,  anorexia, and lethargy.

Phase 2: Hepatic injury. In this stage, there may be a false sense of recovery as GIT symptoms start to improve or disappear. But as hepatotoxicity continues,  abdominal pain or upper quadrant tenderness may surface. At this stage elevation in hepatic enzymes is also noticeable. 

Phase 3: Hepatic failure.  This stage occurs about 3-5 days after post ingestion.  Nausea,  vomiting can reappear. Malaise, jaundice, CNS symptoms including confusion,  somnolence, coma are seen as well. Serious hepatic necrosis occurs and hepatic enzyme levels reach peaks, 10,000 IU/L.  Death due to hepatic failure,  multiple organ system failure,  cerebral edema or sepsis could take place.

Phase 4: Recovery.  Lastly,  stage 4 involves survival and return of full liver function.

Antidote: used is a glutathione mimicking agent, N- acetyl cysteine.

FDA labeling:  In august 2013, consumers were alerted on rare but fatal skin reactions being caused by the drug. Patients experiencing any skin changes were advised to discontinue the drug and consult their physician or a pharmacist.  On January 2014, amount in prescription combined products must be limited to 325mg /tablet or capsule.

Reference: 1. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone Survey. JAMA.

2. Chun LJ, Tong MJ, Busuttil RW,  et al. Acetaminophen hepatotoxicity and acute liver failure.  

3. U.S. Pharmacist.  

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