Acetaminophen Toxicity(paracetamol)

Question 1

toxic doses of acetaminophen

Answer 1

Adults: 7.5-10 g
Children: 150 mg/kg; 200 mg/kg in healthy children aged 1-6 years

Question 2

Signs and symptoms

Answer 2

Most patients who overdose on acetaminophen will initially be asymptomatic, as clinical symptoms of end- organ toxicity do not manifest until 24-48 hours after an acute ingestion. Therefore, to identify a patient who may be at risk of hepatoxicity, the clinician should determine the time(s) of ingestion, the quantity, and the formulation of acetaminophen ingested.

Question 3

Clinical features

Answer 3

Phase 1
0.5-24 hours after ingestion
Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise

Physical examination : pallor, diaphoresis,
malaise, and fatigue

Phase 2
* 18-72 h after ingestion
- right upper quadrant abdominal pain, - -anorexia, nausea, and vomiting
- Right upper quadrant tenderness
- Tachycardia and hypotension may indicate volume losses
- (oliguria)

Phase 3: Hepatic phase
* 72-96 h after ingestion
- Patients have continued nausea and vomiting, abdominal pain, and a tender hepatic edge
Hepatic necrosis and dysfunction may manifest as jaundice,
- coagulopathy, hypoglycemia, and hepatic encephalopathy
- Acute kidney injury develops in some critically ill patients

Death from multiorgan failure may occur

Phase 4: Recovery phase
* 4 d to 3 wk after ingestion
Patients who survive critical illness in phase 3 have complete resolution of symptoms and complete resolution of organ failure

Question 4

Mechanism of Acetaminophen Toxicity

Answer 4

Acetaminophen, also known as paracetamol, is a commonly used over-the-counter pain reliever and fever reducer. While it is generally safe when used at therapeutic doses, an overdose of acetaminophen can cause liver damage and even be fatal. The mechanism of acetaminophen toxicity involves several steps.

1. Metabolism: When acetaminophen is ingested, it is primarily metabolized in the liver. The two major metabolic pathways are glucuronidation and sulfation, which result in the formation of non-toxic metabolites that are eliminated from the body. However, a small portion of acetaminophen is metabolized by a different pathway involving the enzyme cytochrome P450 2E1 (CYP2E1) to form a toxic intermediate called N-acetyl-p-benzoquinone imine (NAPQI).
2. Glutathione depletion: NAPQI is normally detoxified by binding to a molecule called glutathione, which is an antioxidant present in the liver. Glutathione conjugates with NAPQI to form a non-toxic compound that can be safely eliminated from the body. However, in cases of acetaminophen overdose, the production of NAPQI overwhelms the available glutathione stores, leading to depletion of glutathione.
3. Accumulation of NAPQI: When glutathione levels are depleted, NAPQI can bind to cellular proteins, particularly in liver cells, causing oxidative stress, mitochondrial dysfunction, and damage to cellular structures.
4. Liver injury: The accumulation of NAPQI and the resulting oxidative stress and mitochondrial dysfunction can lead to hepatocellular necrosis (death of liver cells). This can ultimately result in liver failure if not promptly treated.

It’s important to note that the severity of acetaminophen toxicity depends on the dose ingested. The risk of liver injury increases significantly with doses above the therapeutic range, especially if taken all at once or in combination with alcohol or certain medications that can potentiate its toxicity.

If someone has taken an overdose of acetaminophen, immediate medical attention is required. Treatment options may include administration of the antidote N-acetylcysteine, which replenishes glutathione stores and helps detoxify NAPQI. Early intervention is crucial to prevent or minimize liver damage.

Question 5

Diagnosis of Acetaminophen Toxicity

Answer 5

The diagnosis of acetaminophen toxicity involves a combination of clinical assessment, history taking, and laboratory tests. Here are the key components of diagnosing acetaminophen toxicity:

1. History and Clinical Assessment: The healthcare provider will begin by obtaining a detailed history, including the amount and timing of acetaminophen ingestion. They will also assess the presence of any symptoms or signs of acetaminophen toxicity, which may include abdominal pain, nausea, vomiting, loss of appetite, jaundice (yellowing of the skin and eyes), and altered mental status.
2. Serum Acetaminophen Level: The measurement of serum acetaminophen concentration is a crucial diagnostic test for acetaminophen toxicity. Blood samples are taken at specific time points after ingestion, typically at 4 hours or more post-ingestion. The results are compared to a nomogram called the Rumack-Matthew nomogram (or a similar graph), which helps determine the risk of hepatotoxicity based on the acetaminophen concentration and time since ingestion. If the serum acetaminophen level exceeds the treatment line on the nomogram, it suggests a higher risk of liver injury.
3. Liver Function Tests (LFTs): LFTs are a group of blood tests that assess liver function and help determine the extent of liver injury. These tests include measurements of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. In acetaminophen toxicity, elevated levels of these enzymes indicate liver damage.
4. Coagulation Profile: Acetaminophen toxicity can affect blood clotting factors synthesized in the liver. Therefore, coagulation tests such as prothrombin time (PT) and international normalized ratio (INR) may be ordered to assess liver function and detect any abnormalities.
5. Other Laboratory Tests: Additional tests may be performed to evaluate the overall health status and rule out other possible causes of liver injury. These may include complete blood count (CBC), renal function tests, and serum electrolytes.

It is important to note that the diagnosis of acetaminophen toxicity should be made promptly, and treatment should be initiated as early as possible to prevent or minimize liver damage. If you suspect acetaminophen overdose or toxicity, it is crucial to seek immediate medical attention.

Question 6

TT

Answer 6

Antidote: N-Acetylcysteine

1)- PO: 140 mg/kg loading dose (max 15 g/dose) followed by

• 70 mg/kg/dose (max 7.5 g/dose) Q4 hours

continue treatment until transaminases and INR have peaked and are decreasing substantially towards normal.

Repeat dose if vomiting occurs within 1 hour of administration.

2)- Intravenous (IV): 150 mg/kg N-acetylcysteine IV loading dose (max 15 g/dose) over 60 minutes,

• followed by 50 mg/kg/dose (max 5 g/dose) over 4 hours,
• followed by 100 mg/kg/dose (max 10 g/dose) over 16 hours for a total infusion time of 21
  hours.

Some patients may require more than 21 hours of N-acetylcysteine administration. See Formulary for weight-based drug dilution volumes.

3. Liver failure: Continue the 100 mg/kg over 16 hours infusion until resolution of encephalopathy, AST less than 1000 units/L, and INR less than 2.