Presentation onParacetamol Poisoning & it’s Management

Name: Samya SayantanId:121-29-381Batch: 7th Sec: ADepartment of PharmacyDaffodil International University

Introduction Paracetamol poisoning is caused by excessive use or

overdose of the analgesic drug paracetamol. Mainly causing liver injury, paracetamol toxicity is one of the most common causes of poisoning. Damage to the liver or hepatotoxicity, results not from paracetamol itself but from one of its metabolites, N-acetyl-p-benzoquinoneimine. NAPQI depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure.

toxicity• Toxicity unlikely to result from a single dose of less

than 150mg/kg in child or 7.5 to 10g for adults.• Toxicity is likely with single ingestions greater than

250mg/kg or those greater tan 12g over 24-hours period.

• Virtually all patients who ingest doses in excess of 350mg/kg develop severe liver toxicity unless appropriately treated.

Signs & Symptoms

The signs and symptoms of paracetamol toxicity occurs in three phases:

Phase-1: 0.5-24 hours after ingestion• Nausea• Vomiting• Pallor• Sweating • Anorexia • Diaphoresis

Phase-2: 18-72 hours after ingestion• develop right upper quadrant abdominal pain.• Acute renal failure.• Multiple organ dysfunction syndrome.

Phase-3: 72-96 hours after ingestion• Hepatic necrosis and dysfunction• Coagulopathy• Hypoglycemia• Hepatic encephalopathy • Cerebral edema• Death

Pathophysiology• Following a therapeutic dose, it is mostly converted to

nontoxic metabolites via Phase II metabolism by conjugation with sulfate and glucuronide , with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 and 3A4 convert 5% of paracetamol to a highly reactive intermediary metabolite, N-acetyl-p-benzoquinoneimine .

• In cases of paracetamol overdose, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration. NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis.

Risk factor• Dose ingested.• Excessive cytochrome P450 activity due to induction

by chronic alcohol or other drug use e.g. carbamazipine, phenytoin, barbiturates.

• Decrease capacity for glucuronidation.• Depletion of glutathione stores due to malnutrition.• The concomitant use of the CYP2E1

inhibitor isniazide increases the risk of hepatotoxicity.

Diagnosis The serum acetaminophen concentration is the basis for

diagnosis and treatment, even in the absence of symptoms, because of the delay in onset of clinical manifestations of toxicity.

Recommended serum studies are follows:• Liver function tests (alanine aminotransferase [ALT],

aspartate aminotransferase [AST], bilirubin) • Prothrombin time (PT) with international normalized ratio

(INR)• Glucose• ECG• Renal function studies (electrolytes, BUN, creatinine)• Lipase and amylase (in patients with abdominal pain)• Salicylate level (in patients with concern of co-ingestants)

.

Management• Activated Charcoal within 2 hours of ingestion

• May reduce absorption by 50 to 90 percent

• Single oral dose of one gram per kilogram

• Inhibits absorption of oral methionine

N-acetylcysteine

The FDA-approved regimen for oral administration of NAC (Mucomyst) is as follows:

• Loading dose of 140 mg/kg• 17 doses of 70 mg/kg given every 4 hours• Total treatment duration of 72 hours

The IV formulation of NAC (Acetadote) is commonly used in many institutions for the treatment of acetaminophen ingestion. Use of the IV formulation of NAC is preferred in the following situations:

• Altered mental status• GI bleeding and/or obstruction• A history of caustic ingestion• Potential fetal acetaminophen toxicity in a pregnant

woman• Inability to tolerate oral NAC because of emesis

refractory to proper use of antiemetics

Liver TransplantationSurgical evaluation for possible liver transplantation is

indicated for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Criteria for liver transplantation include the following:

• Metabolic acidosis• Renal failure• Coagulopathy• Encephalopathy