Introduction
Background
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.
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Acetaminophen is also known as paracetamol and N -acetyl-p-aminophenol (APAP). It is available in the United States as 325-mg and 500-mg immediate-release tablets, and as a 650-mg extended-release preparation marketed for the treatment of arthritis. Various children's dissolvable, chewable, suspension, and elixir formulations of acetaminophen are available. Acetaminophen is a component of many over-the-counter cold and analgesic medications and prescription combinations, including propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet). Hepatotoxicity associated with acetaminophen misuse and overdose is well recognized.
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, malnourishment, or viral illness with dehydration. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.
Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic compounds. These water-soluble conjugates are then eliminated in the urine.
In acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugative pathways of metabolism become saturated. Excess APAP is then 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, NAPQI binds to, and interacts with vital cellular proteins and the lipid bilayer of hepatocyte membranes. An ensuing cascade of oxidative and inflammatory damage can result is hepatocellular death and centrilobular (zone III) 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 the available glutathione to conjugate 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 microvascular effects are associated with a decrease in 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
United States
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 most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure, and it is the second most common cause of liver failure requiring transplantation in the United States.
Mortality/Morbidity
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 oxidative enzyme system, specifically the subfamilies cyp2E1, cyp1A2, and cyp3A4, may be at increased risk of morbidity. Agents that induce this enzyme activity are numerous but 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.
Clinical
History
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 (eg, 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)
- Asymptomatic
- Anorexia
- Nausea or vomiting
- Malaise
- Subclinical rise in serum transaminases levels begins at about 12 hours postingestion
- Phase 2 (18-72 h)
- Right upper quadrant abdominal pain, anorexia, nausea, vomiting
- Continued rise in serum transaminases levels
- Phase 3 (72-96 h)
- Centrilobular hepatic necrosis with continued abdominal pain
- Jaundice
- Coagulopathy
- Hepatic encephalopathy
- Nausea and vomiting
- Renal failure
- Fatality
- Phase 4 (4 d to 3 wk)
- Complete resolution of symptoms
- Complete resolution of organ failure
Physical
Physical examination findings vary, depending on the phase of toxicity.
- Phase 1
- Pallor
- Malaise
- Vomiting
- Diaphoresis
- Phase 2
- Right upper quadrant abdominal tenderness
- Tachycardia
- Hypotension
- Phase 3
- Tender hepatic edge
- Jaundice
- Evidence of coagulopathy, including gastrointestinal (GI) bleeding
- Evidence of hepatic encephalopathy
- Phase 4: Resolution
Causes
- Production of acetaminophen's toxic metabolite, NAPQI, in excess of an adequate store of conjugating glutathione is associated with hepatocellular damage, necrosis, and hepatic failure.
- Additional mechanisms of acetaminophen-induced toxicity are postulated as well.
More on Toxicity, Acetaminophen |
 Overview: Toxicity, Acetaminophen |
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| Treatment & Medication: Toxicity, Acetaminophen |
| Follow-up: Toxicity, Acetaminophen |
| References |
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References
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Further Reading
Keywords
acetaminophen toxicity, paracetamol, N-acetyl-p-aminophenol, APAP, analgesic agent, antipyretic agent, N-acetyl-p-benzoquinone-imine, NAPQI, hepatocellular death, hepatocellular necrosis, centrilobular liver necrosis, N -acetylcysteine, NAC, fulminant hepaticfailure, hepatic encephalopathy, renal failure, coagulopathy, diaphoresis, acetaminophen toxicity, acetaminophen overdose, APAP toxicity, APAP overdose, hepatotoxicity, acetaminophen poisoning, APAP poisoning
