Acetaminophen (APAP) is a non-opioid analgesic and antipyretic agent used to treat pain and fever. It is used as a single agent for mild to moderate pain and in combination with an opioid analgesic for severe pain.
Acetaminophen, also called N-acetyl para-aminophenol or paracetamol is one of the most widely used over-the-counter analgesic and antipyretic agents . Although its exact mechanism of action remains to be elucidated, it is historically categorized as a NSAID because it inhibits the cyclooxygenase (COX) pathways . Like other NSAIDs, acetaminophen has analgesic and antipyretic properties. However, studies have shown that acetaminophen lacks peripheral anti-inflammatory properties. It may be that acetaminophen inhibits the COX pathway in the central nervous system but not peripheral tissues. Additionally, acetaminophen does not appear to bind to the active site of either the COX-1 or COX-2 enzyme, instead of reducing the activity of COX by a different mechanism. It also has been theorized that acetaminophen inhibits a splice variant of COX-1, also called COX-3, but this has not been confirmed to occur in humans . Regardless, the reduction of the COX pathway activity by acetaminophen is thought to inhibit the synthesis of prostaglandins in the central nervous system, leading to its analgesic and antipyretic effects. The analgesic properties may be due to a stimulating effect on the descending serotonergic pathways in the central nervous system (CNS). Other studies have suggested that acetaminophen or one of its metabolites also can activate the cannabinoid system, contributing to its analgesic action.
Acetaminophen can be administered orally, rectally, or intravenously (IV) .
Oral: Acetaminophen is available as a tablet, capsule, syrup, oral solution, or suspension.
Rectal: Acetaminophen is available as a rectal suppository for both adult and pediatric patient populations.
Intravenous: Acetaminophen can be administered as an IV infusion.
Adverse effects of acetaminophen administered orally or rectally may include the following
Additional adverse effects of acetaminophen administered intravenously include nausea, vomiting, constipation, pruritus, and abdominal pain.
Rare but serious adverse effects include hypersensitivity and anaphylactic reactions as well as serious and even fatal skin reactions. These include toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome.
US Boxed Warnings
Acetaminophen use has been linked to liver failure and sometimes has led to liver transplant or death. The hepatotoxicity seen with acetaminophen use is typically associated with high doses of acetaminophen that exceed the recommended maximum dose . This may involve the intake of more than one drug product that contains acetaminophen as an ingredient. Liver damage also has been seen in patients with chronic dosing of acetaminophen.
There is also a US boxed warning to avoid dosing errors, particularly when administering acetaminophen to pediatric patients, as well as making sure that the maximum total daily dose of acetaminophen does not exceed the recommended maximum when taking into account all medications that contain acetaminophen.
Although these effects, warnings and associations have been documented, acetaminophen remains a safe and effective medication when used properly. The current manufacturer dose recommendation is limited to 3 grams in 24 hours. However, toxicity is rare at less than 150 mg/kg for an adult or 200 mg/kg for a child.
Contraindications to the use of acetaminophen include hypersensitivity to acetaminophen, severe hepatic impairment, or severe active hepatic disease. However, it is generally debated among experts if hepatic impairment is truly a limiting factor, as it would likely be associated with decreased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).
Patients being treated with acetaminophen should be monitored for desired clinical effects, such as pain or fever relief. Serum concentrations are unnecessary when dosed properly. In overdose settings, laboratory evaluation is necessary. In acute overdoses, in which an ingestion occurs over less than eight hours, a serum APAP concentration should be assessed and plotted on the Rumack-Matthew Nomogram, with the time course starting at the onset of ingestion, in order to determine toxicity and need for treatment. Nonacute ingestions require assessment of acetaminophen concentration and transaminases, and treatment should occur.
Additionally, caution should be used in patients with renal or hepatic impairment or patients with the alcoholic liver disease, glucose six phosphate dehydrogenase deficiency, or severe hypovolemia. However, there is evidence that acetaminophen may be safe to use in the setting of alcoholic liver disease .
Acetaminophen can cross the placental barrier, but there is no evidence of increased teratogenic effects due to the use of normal doses of acetaminophen during pregnancy . Acetaminophen also is excreted into breast milk, but adverse reactions in nursing infants have not been widely observed.
Acetaminophen is responsible for an estimated 500 deaths and 50,000 emergency department visits in the United States each year . It is the most common drug-related cause of acute liver failure. The mechanism of hepatic injury is due to the drug metabolism properties of acetaminophen . Following therapeutic levels of oral acetaminophen, 60% to 90% of the drug is metabolized in the liver to glucuronic acid- and sulfate-conjugate metabolites. A smaller fraction (approximately 5% to 15%) is metabolized by the cytochrome P450 system (CYP450). Metabolism primarily via CYP2E1results in the formation of the toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). Normally, NAPQI is neutralized by glutathione to nontoxic metabolites. However, with excessive doses of acetaminophen, the normal phase II drug metabolism pathways become saturated, and a higher dose of acetaminophen is metabolized by the CYP450 pathway. This results in high levels of NAPQI formation, and the limited glutathione stores can become depleted. Without glutathione, NAPQI levels build up and NAPQI, as a reactive intermediate, can react with cellular macromolecules, proteins, lipids, and nucleic acids. This can lead to centrilobular (Zone 3) hepatic injury and hepatocellular death.
The only approved antidote for acetaminophen overdose and toxicity is N-acetylcysteine (NAC) . NAC is a precursor to glutathione synthesis and helps to restore the intracellular stores of glutathione to neutralize the NAPQI compound. N-acetyl cysteine can be administered orally or by IV. IV N-acetyl cysteine is typically preferred because vomiting is common with acetaminophen overdose. It is effective if administered within the first few hours (up to 8 to 10 hours) of toxic ingestion of acetaminophen. N-acetyl cysteine is administered as a 20-hour IV protocol or 72-hour oral protocol, and the AST/ALT of the patient should be monitored during treatment . One important thing to keep in mind is that most patients do not have symptoms in the first few hours of ingestion of toxic levels of acetaminophen and may only have abdominal pain and nausea as symptoms for the first 12 to 24 hours. Between 24 and 72 hours, these symptoms may dissipate, although AST/ALT levels may be abnormal. Patients who present more than 24 hours following ingestion of toxic levels of acetaminophen may have symptoms such as nausea, vomiting, jaundice, abdominal pain, and hypotension. These patients may require airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema or other symptoms as they arise.
Acetaminophen toxicity is typically managed with an interprofessional team of physicians, nurses and pharmacists. Specific procotols have been designed to direct a multi-disciplinary team of healthcare providers when patients present to emergency rooms with acute acetaminophen toxicity. One such protocol was designed by emergency physicians, nurses, toxicologists, pharmacists and psychiatrists . Dentists can also become involved if the overdose is secondary to dental procedures . Importantly, upon discharge patients should be provided with clear instructions on APAP medication management (Level V).