PARACETAMOL TOXICITY : HOW TO KNOW ABOUT PARACATMOL TOXICITY (ACETAMINOPHEN)

 

PARACETAMOL TOXICITY :

Metabolism:

the metabolism of acetaminophen, identify the key toxic metabolite, describe the clinical presentation of acetaminophen toxicity, and discuss the treatment and antidote for acetaminophen toxicity. We will start with a general discussion about acetaminophen and then talk about its pharmacology and metabolism and how this applies

to acetaminophen toxicity. We'll then discuss the clinical presentation and finally the treatment for acetaminophen toxicity.

About Paracetamol:

Acetaminophen is one of the most commonly used analgesics in antipyretics today.

It is in many over-the-counter medications as well as in many prescription medications in combination with various opioids.

Because of this, in addition to acetaminophen toxicity, you must consider toxicity from other medications in acute and chronic ingestions. Many consider acetaminophen to be a benign medication. However, it is the most common cause of acute fulminate liver

failure in the United States.

Overdose:

In overdose, it can be fatal, cause hepatic necrosis and fulminate liver failure that requires transplantation.

Absorption:

Acetaminophen is rapidly absorbed by the GI tract. 97% is metabolized by the liver, and the remaining 3% is excreted

unchanged in the urine. Of the 97% metabolized by the liver, 94% goes through either glucuronidation or sulfation and then gets excreted in the urine.

The remaining 3% is metabolized by the P450 system to a metabolite called NAPQI.

Cause of Toxicity:

This is the metabolite that causes the heap toxicity seen in acetaminophen overdose. NAPQI is rapidly metabolized by glutathione in the liver to non-toxic metabolites which get excreted in the urine. When acetaminophen is ingested in large doses, the metabolism of NAPQI depletes glutathione stores. When glutathione levels reach 30% or less, the hepatotoxic effects of NAPQI begin to take place.

Precaution:

Patients with chronic liver disease, malnutrition, or alcoholism are much more sensitive to the effects of NAPQI. And hepatotoxicity can be seen

in lower-dose ingestions of acetaminophen. This is mainly because these patients are deficient in glutathione.

The clinical presentation takes place in four stages.

Stage 1 presents with very nonspecific constitutional and GI symptoms, which can make the diagnosis especially challenging if the patient does not volunteer information on acetaminophen ingestion. This stage lasts for up to 24

hours post-ingestion.

Stage 2, the hepatotoxic effects of NAPQI BDN. Clinical hepatitis develops with rising liver enzymes, right upper quadrant pain, and right upper quadrant tenderness on exam.

Typically, blood levels of acetaminophen are low at this point, because it has been completely

metabolized. Serum drug tests test only for acetaminophen and not the metabolites of acetaminophen. This stage is seen between 24 hours and 48 hours post-ingestion.

Stage 3 is the point of maximum toxicity. Liver enzymes peak at 10,000 to 20,000. Other causes of acute hepatitis,

such as viruses and alcohol, usually do not result in profound transaminitis like acetaminophen toxicity. Other signs of liver failure also begin to appear, such as encephalopathy or coagulopathy. This is typically seen on days 3 and 4 post-ingestion.

Stage 4 is either a recovery phase, with the return of normal liver function and no long-term damage, or a stage where patients go into fulminant hepatic failure and can require transplantation. This stage lasts up to two weeks post-ingestion. Typically, acetaminophen toxicity takes place in injections that are greater than 150 milligrams per kilogram in children and greater than 7 and 1/2 to 10 grams in adults.

Treatment:

When deciding if treatment with an N-acetylcysteine, which is the antidote, is necessary,

we use the Rumack-Matthew nomogram. This nomogram is based on the acetaminophen level at four hours or greater post-ingestion as well as the half-life of acetaminophen. Luckily, acetaminophen overdose does have an antidote, which is the mainstay of treatment.

This is N-acetylcysteine or NAC for short. This is metabolized to precursor glutathione, which can then be used to metabolize the toxic NAPQI. It is 100% effective if given within eight hours of ingestion, making this diagnosis especially time-sensitive. Gastric lavage and the use of ipecac to induce vomiting are no longer recommended, mainly because of the risk of aspiration and causing pneumonitis. GI decontamination with activated charcoal can be used in large ingestions if the patient presents within two hours. This is the Rumack-Matthew nomogram.

It is based on a level of acetaminophen at four hours or greater and the half-life of acetaminophen. So this nomogram is divided into three areas.

The area above line 1 represents probable toxicity. If a patient falls above this line on their acetaminophen level, they will likely go on to develop hepatotoxicity, and all these patients should be started on NAC therapy.

The area below line 2 represents no toxicity and patients that should not go on to develop hepatotoxicity from NAPQI.

So these patients do not need

to be treated.

Patient History:

Keep in mind that patients with alcoholism, malnutrition and chronic liver disease can have toxic ingestions at lower doses.

So, if those patients are in the possible or probable toxicity levels, you might want also to still consider treating them with an N-acetylcysteine.

So basically, NAC should be administered in three situations.