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Acetaminophen

Acetaminophen is one of the most commonly used analgesic and anti-pyretic agents. The foremost brand is Tylenol, but acetaminophen is present in more than 200 brand name analgesics. It is available in tablet, caplet, liquid and suppository form. Absorption is rapid and therapeutic levels are obtained within 40 to 120 minutes after ingestion. Peak levels are reached within 2 to 4 hours after ingestion. The potentially toxic dose for an adult is only about 10 fold higher than the usual therapeutic dose of 650 to 1000 mg. For this reason, acetaminophen is one of the most common drugs involved in accidental or intentional overdoses.

Clinically, acetaminophen overdose has 4 recognized stages:

Stage

Time

Symptoms

1

First 24 hours

Nausea, vomiting, anorexia, diaphoresis

2

24 to 48 hours

RUQ tenderness, elevated transaminases

3

Day 3 to 4

Jaundice, coagulopathy, renal failure, encephalopathy, hypoglycemia

4

Day 4 to 14

Death or recovery

Doses greater than 7.5 g in an adult (23 regular strength or 15 extra strength tablets) or 140 mg/kg body weight in a child can be toxic. Tylenol’s label warns of the hazards of dosages greater than 4 g in 24 hours and also of concurrent alcohol consumption. Chronic use of alcohol or drugs, such as barbiturates or isoniazid, increases susceptibility.

Most acetaminophen is metabolized in the liver by conjugation with sulfate or glucuronic acid; only a small fraction is metabolized by cytochrome P-450 dependent oxidases into reactive intermediates such as N-acetyl-p-benzoquinoneimine and superoxide anions. The low levels of intermediates produced by therapeutic doses are immediately quenched by combination with glutathione. In an overdose, large amounts of these reactive intermediates overwhelm glutathione stores and cause hepatocellular necrosis and liver failure. Rapid diagnosis and treatment is essential to prevent hepatocellular necrosis.

Obtaining an accurate time of ingestion is a critical factor in accurately interpreting serum acetaminophen levels. A single blood sample should be collected at least 4 hours after ingestion to ensure that the absorptive phase is complete. The result is then plotted on a Rumack-Matthew nomogram to assess the risk of hepatotoxicity (Arch Intern Med 1981; 141:382). The upper broken line is called the “probable toxicity line” and represents the cutoff level at which 60% of patients above the line would develop severe hepatotoxicity. The solid line below is the “possible toxicity line”; 25% of patients between this line and the probable toxicity line develop severe hepatotoxicity. If the acetaminophen level lies above the broken line, a full course of acetylcysteine therapy is usually administered. If the level falls below the broken line, treatment is usually not necessary or can be discontinued. This nomogram is limited to a single acute ingestion identified within 24 hours of the overdose. Overdoses with enteric coated or sustained-released acetaminophen do not follow the Rumack nomogram.

For children who have ingested liquid acetaminophen elixir, treatment decisions may be reliably made at hours post ingestion since absorption is so rapid. The suggested treatment threshold at two hours is an acetaminophen plasma level of 225 ug/mL.

If the time of ingestion is unknown, two serum levels should be drawn during an 8 hour period. If the half-life exceeds 4 hours, hepatotoxicity is likely. It may be necessary to draw a 12-hour sample to determine serum half-life in patients taking multiple drugs. Some co-ingestants, such as alcohol, slow GI motility, thereby increasing both the severity and duration of acetaminophen levels. Anticonvulsants also increase the toxicity of acetaminophen.

Therapeutic range is;

0 - 12 years old

10 - 20 ug/mL

>12 years old

0 - 49 ug/mL

Specimen requirement is one SST or one green top (heparin) tube of blood.

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