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Acetaminophen Toxicity

Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning. Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen also is known as paracetamol and N-acetyl-p-aminophenol (APAP). Acetaminophen is also a component of many over- the-counter medications and prescription combinations, such as propoxyphene-acetaminophen (e.g.: Darvocet) and oxycodone-acetaminophen (e.g.: Percocet).

Pathophysiology
The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults. The at-risk dose may be lower in some susceptible patient populations, such as persons with alcohol abuse. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small. In acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugative pathways of metabolism in the liver become saturated. Excess APAP is oxidatively metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, N-acetyl-p- benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation or reduced glutathione stores, the end result is hepatocellular death and centrilobular liver necrosis.

The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and increases glutathione availability to bind to NAPQI. It may also enhance sulfate conjugation of any unmetabolized APAP. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations, and this vasodilatory effect on microcirculatory blood flow enhances local oxygen delivery to peripheral tissues. These vasodilating effects decrease morbidity and mortality even in the setting of established hepatotoxicity.

NAC is most effective when administered within 8 hours of ingestion. When indicated, however, NAC should be administered regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure, even in the absence of measurable serum acetaminophen levels.

Frequency/Morbidity/Mortality
Acetaminophen is one of the most common pharmaceutical agents involved in overdose, as reported to the American Association of Poison Control Centers. APAP toxicity is the second most common cause of hepatic failure requiring liver transplantation in the United States.

The majority of patients with APAP overdose survive with supportive care alone, in conjunction with antidotal therapy. If correctly treated in a timely manner, most patients do not suffer significant sequelae. Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or liver transplantation occurs in less than one half of these patients. Patients with malnutrition, AIDS, chronic ethanol abuse, or anorexia nervosa may be at increased risk for morbidity because of deficient glutathione stores and inadequate detoxification of NAPQI. Patients with enhanced ability to make NAPQI due to induction of the P450 system, specifically cyp2E1, may be at increased risk of morbidity. The agents that induce this enzyme activity include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or chronic ethanol ingestion. Pediatric patients younger than 5 years appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate acetaminophen, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported any alternative pediatric therapy, treatment in children should be the same as in adults.

History/Physical
The course of acetaminophen toxicity generally is divided into 4 phases. Clinical evidence of end-organ (hepatic, renal) toxicity is often delayed 24-48 hours postingestion. Because antidotal therapy is most effective when initiated within 8 hours postingestion, the clinician must obtain an accurate history of the time(s) of ingestion, the quantity, and formulation of acetaminophen ingested, and any co-ingestants, which may delay APAP absorption (e.g.: anticholinergic drugs or opioids). Because a patient’s history may be inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms. After a single ingestion, NAC therapy is guided by the serum APAP concentration.

  • Phase 1 (0-24 h): loss of appetite, vomiting, general malaise
  • Phase 2 (24-72 h): abdominal pain, increased liver enzymes
  • Phase 3 (72-96 h): liver necrosis, jaundice, encephalopathy, renal failure, death
  • Phase 4 (>4d -3 weeks h): complete resolution symptoms and organ failure

Physical findings range from malaise to vomiting, abdominal pain, diaphoresis, tachycardia, hypotension, jaundice, GI bleeding, coagulopathy, hepatic encephalopathy.

Lab Studies
A serum acetaminophen level drawn 4 or more hours after a single ingestion may be plotted on the Rumack- Matthew nomogram in order to guide therapy. The nomogram is not applicable after multiple or chronic ingestions. Liver enzymes and coagulation factors should be tracked, as should serum ammonia. The patient should have a chem panel and CBC and should be typed and crossed. Renal functions and a urine analysis should be obtained.

Treatment
If treatment occurs within a few hours of ingestion, gastric contamination with oral activated charcoal should be initiated since it readily absorbs acetaminophen. N-acetylcysteine (NAC) if given within 8 hours of ingestion is virtually 100% hepatoprotective. It is also indicated in long term chronic cases and can be given orally or intravenously even in children over 80 pounds.

Medical-Legal Considerations
Failure to administer NAC because of a possible late presentation could be medically and legally risky. It is always best to give a dose of NAC when in question and not to delay this administration. Failure to consider and evaluate for possible co-ingestants could be a major pitfall so a thorough history is essential. When in doubt it is always best to contact the regional poison control center for further direction of treatment.

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