The Learning Blog

More than a month ago, the United States Food and Drug Administration (USFDA) Advisory Committee held a meeting in Maryland, USA in order to address the problem of liver injury related to the use of paracetamol (or acetaminophen) in both over-the-counter (OTC) and prescription drugs.

Acetaminophen (para-acetylaminophenol) is a commonly-used analgesic and antipyretic medicine. The name “acetaminophen” and “paracetamol” (from para-acetylaminophenol) can be used interchangeably. Wikipedia uses “paracetamol” as the subject name and redirects users to this page for those using “acetaminophen” as a search term.

The USFDA, in its Advisory Committee Report published 7 July 2009, warned consumers that paracetamol, though safe in recommended doses, is also an important cause of serious liver injury. This drug is highly favored for cases of mild-to-moderate pain and fever due to its low potential to cause gastric irritation (gastritis), stomach bleeding, abdominal discomfort, among others side-effects very commonly seen in non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin.

However, paracetamol, when taken beyond the safe dosage, causes liver injury resulting to abnormal liver function tests (e.g. aspartate transaminase or AST, alanine transaminase or ALT, alkaline phosphatase or ALP, and others), acute liver failure, and even death. An unintentional overdose is usually seen in patients taking a combination of two or more products containing paracetamol for a total amount greater than 4 grams.

In the United States, it was found that from 1998 to 2003, paracetamol-related liver injury was the number one cause of acute liver injury; from this, more than 50% was brought about by unintended overdose. Similar numbers of unintentional overdose were seen in 2007.

Other ways that a patient might get liver injury from paracetamol intake are intentional overdose (suicidal), patients with pre-existing liver conditions, and patients taking paracetamol with other liver-toxic drugs and substances (antibiotics, anticholesterol drugs especially statins, and alcohol).

In the United Kingdom, mortality from paracetamol overdose fell from 148 deaths in 1991 (alone and in combination) to 98 deaths 2004. A contributing factor to the reduction of deaths in the UK is a legislation that restricts the number of tablets allowed in a pack and the maximum number of tablets allowed in an over-the-counter sale.

The USFDA report explained as to how paracetamol destroys the liver. This is through the excess production of a toxic metabolite after a high intake of the drug. This toxin binds with liver proteins which eventually causes liver cell injury. The severity of this injury depends on how rapid the detoxification process is by the liver.

This toxic metabolite the report mentioned, but never specifically named, is N-acetyl-para-benzo-quinone imine or NAPQI. Paracetamol is metabolized to non-toxic products in the liver by three ways: (1) Paracetamol is excreted unchanged in less than 5%; (2) 50% is changed by the addition of glucuronic acid; (2) 20-40% by the addition of a sulfate; and (3) 15% or less through the formation of NAPQI then detoxified by the addition of glutathione.

In cases of overdose, the glucuronic acid, sulfate, and glutathione reserves in the liver are immediately consumed with no fast way to replenish the stores.  Thus, NAPQI levels increase in a period of time leading to not only liver injury but affecting the kidneys as well.

The USFDA lists down the reasons as to why paracetamol overdoses occur:

• Taking just a small amount of acetaminophen over the recommended total daily dose (4 grams per day) may lead to liver injury. Problems with recognizing and treating toxicity include delay of onset, toxicity can mimic flu-like symptoms, and the antidote, N-acetylcysteine, is effective if given early.
• Some individuals may be especially sensitive to liver injury from acetaminophen. The maximum safe dose may not be the same for all persons.
• There is a variety of paracetamol products with different strengths used in a range of doses for various indications. It is very much advised to read the label for the presence and the amount (if available) of the drug before taking it especially for those over-the-counter medications.
• Finally, the association between acetaminophen and liver injury is not common knowledge. Consumers are not sufficiently aware that acetaminophen can cause serious liver injury, and their perceptions may be influenced by the marketing of the products.

The antidote for paracetamol overdose is giving N-acetylcysteine or NAC by mouth. NAC does not directly act on NAPQI but prevents toxicity by limiting NAPQI formation and increases the capacity to detoxify formed NAPQI by increasing the glutathione reserves in the liver. NAC is only effective less than 24 hours after ingestion. As an aside, NAC is also used as a mucolytic agent by inhalation.

Tips on using Paracetamol:

• Read all the information given to you by your doctor and follow directions.
• Read the information on the OTC “Drug Facts” label or on the prescription label and follow directions.
• Be sure you understand the following:
  - the dose, which is how much acetaminophen you can take at one time
  - how many hours you must wait before taking another dose of acetaminophen
  - how many doses of acetaminophen you can take safely each day
  - when to stop taking acetaminophen and ask a doctor for help
• Never take more than directed, even if your pain or fever isn’t any better. Taking more acetaminophen than directed can put you at risk for liver damage.
• Never take more than one medicine that contains acetaminophen. Check the active ingredients of all your medicines to make sure you are taking no more than one medicine containing acetaminophen at a time.

Other useful information:

Sources:

1. United States Food and Drug Administration. Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee: Meeting Announcement. Rep. United States Food and Drug Administration, 7 July 2009. Web. 9 Aug. 2009. <http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm>.
2. United States Food and Drug Administration. “Acetaminophen and Liver Injury: Q & A for Consumers.” U S Food and Drug Administration Home Page. 24 June 2009. Web. 09 Aug. 2009. <http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm168830.htm>.
3. “Paracetamol -.” Wikipedia, the free encyclopedia. Web. 09 Aug. 2009. <http://en.wikipedia.org/wiki/Paracetamol>.
4. Rella, Joseph. “Acetaminophen and Salicylates: Toxicity and Management.” Lecture. New Jersey Medical School. New Jersey Poison Information & Education System. Web. 9 Aug. 2009. <http://www.njpies.org>.

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