Indications:

Short-term analgesic and antipyretic:

• minor myalgia: physical exertion, common cold
• backache
• headache
• toothache
• menstrual cramps
• minor pain of arthritis
• fever

Mechanism of action

How acetaminophen produces analgesia is not known. Several theories have been advanced but none have been supported by sufficient evidence.

Acetaminophen Toxicity

Acetaminophen has fewer side effects than do NSAIDs. It has no effect on platelet function, rarely causes gastrointestinal problems, and can be given to individuals who cannot take aspirin or other NSAIDs. However, acetaminophen can produce severe hepatotoxcity or liver damage in some patients, even at recommended therapeutic doses.

The liver oxidizes acetaminophen to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI).* At normal therapeutic dosage any NAPQI produced is rapidly neutralized by glutathione. Glutathione is the chief hepatocellular anti-oxidant. Neutralizing NAPQI depletes available stores of glutathione. If the amount of NAPQI exceeds available glutathione the hepatocyte is exposed to oxidative damage which can cause inflammation or cell death. Glutathione is also consumed in the process of neutralizing the metabolic by-products of ethanol. Therefore, consuming ethanol with acetaminophen increases the toxicity of acetaminophen or any other source of oxidative stress.

If acetaminophen overdose is suspected, intravenous administration of N-acetylcysteine (NAC) is the first line of treatment (oral route NAC is poorly absorbed and may cause N/V). NAC assists remaining hepatocytes to replace glutathione required to reduce further oxidative stress. It does this by providing the glutathione precursor cysteine. If the acetaminophen overdose occurred within 4 hours, activated charcoal may be given just before starting NAC.

Patients with an INR >2 or a Grade 2 hepatic encephalopathy (HE) or whose prognosis is poor due to age and etiology should be considered for transfer to a liver transplant center where experienced professionals can evaluate for transplant listing.* Multi-organ system failure (MOSF) often complicates acute liver failure.

While waiting for transport to a Transplant Center:

• avoid sedatives if possible
• monitor: acetaminophen levels, Arterial pH, lactate, Na, ammonia, glucose, I/O
• cerebral edema suspected, monitor serum osmolarity, elevate head of bed 30^o, mannitol RX
• endotracheal intubation grade 4 HE

Patients at greatest risk of hepatotoxicity when taking acetaminophen include:

• People who consume large amounts of alcohol (more than 3 alcoholic beverages a day). Since 1998, the FDA has required alcohol warnings for acetaminophen and other nonprescription (over-the-counter) analgesics.
• Individuals who are malnourished or fasting
• Patients with preexisting liver disease
• Individuals who are also using other drugs that can cause liver damage
• Exceed 4 gms or 4000 mg in a 24-hour period.

There are multiple trade names of acetaminophen-containing medications, including both prescription and over-the-counter drugs. As a result, patients may accidentally take higher-than-recommended doses of acetaminophen. Therefore, patients should be taught to look for acetaminophen in prescription and over-the-counter analgesics, and other types of medications such as cold remedies. The FDA has requested manufacturers to limit individual unit doses to 325mg.

In 2011, the FDA provided the following safety recommendations for healthcare professionals:

• Advise patients not to exceed the acetaminophen maximum total daily dose (4 grams/day).
• Severe liver injury, including cases of acute liver failure resulting in liver transplant and death, has been reported with the use of acetaminophen.
• Educate patients about the importance of reading all prescription and OTC labels to ensure they are not taking multiple acetaminophen-containing products.
• Advise patients not to drink alcohol while taking acetaminophen-containing medications.
• Rare cases of anaphylaxis and other hypersensitivity reactions have occurred with the use of acetaminophen. A new "Black Box Warning" is required to be part of packaging.
• Advise patients to seek medical help immediately if they have taken more acetaminophen than directed or experience swelling of the face, mouth, and throat, difficulty breathing, itching, and rash.
• Report adverse events to FDA's MedWatch program.

In 2012, the manufacturer of Tylenol^® lowered the maximum adult daily dose to 3 grams/day. Concern that 4 grams/daily FDA recommended maximum adult dose could increase the risk of hepatotoxicity for some individuals.

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