Acetaminophen


Article Author:
Valerie Gerriets


Article Editor:
Thomas Nappe


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/16/2019 10:20:17 AM

Indications

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. 

Mechanism of Action

Acetaminophen, also called N-acetyl para-aminophenol or paracetamol is one of the most widely used over-the-counter analgesic and antipyretic agents [1]. Although its exact mechanism of action remains to be elucidated, it is historically categorized as a NSAID because it inhibits the cyclooxygenase (COX) pathways [0][3]. 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 [0]. 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.    

Administration

Acetaminophen can be administered orally, rectally, or intravenously (IV) [5].

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

 Adverse effects of acetaminophen administered orally or rectally may include the following

  • Skin rash, hypersensitivity reactions
  • Nephrotoxicity (elevations in BUN, creatinine)
  • Hematological: anemia, leukopenia, neutropenia, pancytopenia
  • Metabolic and Electrolyte
    • Decreased serum bicarbonate
    • Decreased levels of sodium and calcium
    • Hyperammonemia
    • Hyperchloremia
    • Hyperuricemia
    • Increased serum glucose
    • Increased bilirubin and alkaline phosphatase

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

Hepatotoxicity:

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 [6]. 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.

Injection:

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

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). 

Monitoring

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 [7].

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 [0]. Acetaminophen also is excreted into breast milk, but adverse reactions in nursing infants have not been widely observed.

Toxicity

Acetaminophen is responsible for an estimated 500 deaths and 50,000 emergency department visits in the United States each year [0]. 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 [0]. 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) [11]. 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 [12]. 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.

Enhancing Healthcare Team Outcomes

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 [13].  Dentists can also become involved if the overdose is secondary to dental procedures [14].  Importantly, upon discharge patients should be provided with clear instructions on APAP medication management (Level V).


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Acetaminophen - Questions

Take a quiz of the questions on this article.

Take Quiz
Acetaminophen fits into which FDA category of drug labeling classification?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the correct single dose of oral acetaminophen in a child weighing 12 kg?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How does acetaminophen exert its effect?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Acetaminophen interferes with the excess release of prostaglandins by inhibiting which enzyme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the maximum daily dose of acetaminophen in adults according to the FDA?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the active ingredient in Tylenol?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which medication has the least anti-inflammatory effect?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A mother brings her son who has asthma to the pulmonary clinic. She would like to know if she can give her child acetaminophen. She has heard reports that it may worsen asthma. What is the current consensus on acetaminophen and asthma?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Acetaminophen has come under recent scrutiny for its potentially lethal effects if dosed improperly. What is the pathological event that typically accompanies acetaminophen overdose?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is a good recommendation for a patient who complains of muscle aches and joint pain, but says that ibuprofen upsets her stomach?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
In the hospital, nurses frequently administer acetaminophen to clients. Which of the following is true about this medication? Select all that apply.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Acetaminophen is preferred over aspirin in which of the following scenarios? Select all that apply.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Acetaminophen - References

References

Bunchorntavakul C,Reddy KR, Acetaminophen-related hepatotoxicity. Clinics in liver disease. 2013 Nov     [PubMed]
Smith HS, Potential analgesic mechanisms of acetaminophen. Pain physician. 2009 Jan-Feb     [PubMed]
Bannwarth B,Péhourcq F, [Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues]. Drugs. 2003     [PubMed]
    [PubMed]
Zimmerman HJ,Maddrey WC, Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology (Baltimore, Md.). 1995 Sep     [PubMed]
Smilkstein MJ,Knapp GL,Kulig KW,Rumack BH, Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) The New England journal of medicine. 1988 Dec 15     [PubMed]
Prescott LF, Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Archives of internal medicine. 1981 Feb 23     [PubMed]
Beauchamp GA,Hart KW,Lindsell CJ,Lyons MS,Otten EJ,Smith CL,Ward MJ,Wright SW, Performance of a multi-disciplinary emergency department observation protocol for acetaminophen overdose. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2013 Sep     [PubMed]
    [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Neurology. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Neurology, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Neurology, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Neurology. When it is time for the Neurology board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Neurology.