Acetaminophen toxicity

Introduction

• acetaminophen (N-acetyl-p-aminophenol; APAP; paracetamol)

• The most widely used analgesic-antipyretic in the United States.

• Acetaminophen is a component of hundreds of over-the-counter and prescription medications used worldwide.

• Although the drug is remarkably safe when taken at usual therapeutic doses, overdose of acetaminophen has been recognized since 1966 to cause fatal and nonfatal hepatic necrosis .

• It is suspected that even repeated therapeutic or slightly excessive doses can be hepatotoxic in susceptible individuals, such as alcoholics .

• Acetaminophen poisoning has become the most common cause of acute liver failure in the United States

•  Acetaminophen is available in both immediate-release and sustained-release formulations .

• The therapeutic dose is 10 to 15 mg/kg per dose in children and 325 to 1000 mg per dose in adults, given every four to six hours, with a maximum recommended daily dose of 80 mg/kg in children or 4 g in adults.

• The toxic dose may vary among individuals according to baseline glutathione levels and other factors ..

• Toxicity is unlikely to result from a single dose of less than 150 mg/kg in a child or 7.5 to 10 g for an adult ..

• Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period..

• Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peak aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 1000 IU/L) unless appropriately treated ..

Pharmacokinetics

Absorption

• is rapidly and completely absorbed from the gastrointestinal tract.

• Serum concentrations peak between one-half and two hours after an oral therapeutic dose

• Peak serum concentrations are reached within four hours following overdose of immediate-release preparations, but may be delayed beyond four hours when drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested or following overdose of extended releases preparations

• Therapeutic serum concentrations range from 10 to 20 mcg/mL.

Elimination

• Elimination half-lives range from two to four hours for all acetaminophen preparations,

• the elimination phase may be delayed in onset for extended-release preparations due to prolonged tablet dissolution and absorption.

• Half-lives greater than four hours have been noted in patients with hepatotoxicity

• NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, forming NAPQI-protein adducts .This process is irreversible and leads to oxidative injury and hepatocellular centrilobular necrosis

• The centrilobular region (zone III) is preferentially involved because it is the area of greatest concentration of CYP2E1 and therefore the site of maximal production of NAPQI.

Clinical factors influencing toxicity

*** Liver damage from acetaminophen ingestion can occur in four circumstances:

• Excessive intake of acetaminophen• Excessive cytochrome P450 activity• Decreased capacity for glucuronidation or

sulfation• Depletion of glutathione stores

• Others ::: concomitant use of alcohol or other drugs, comorbid illnesses, advancing age, genetic makeup, and nutritional status

Others

Alcohol use Acute “protective” compete on Cytp450

Chronic Increase if multiple doses “activate Cyp2E1” + deplete

glutathione

Medications 1. That ↑ Cyp2E1 activity (anticonvulsants + Anti Tb”

2. Compete on Glucoronidation

3. Herbals

Nutritional states Malnutrition

Age Elderly Higher risk

Tobacco Cyp2A1 inducer

Rumack Nomogram lines defines high risk groups

Clinical presentation

• The initial manifestations of acetaminophen poisoning are often mild and nonspecific, and do not reliably predict subsequent hepatotoxicity

Four subsequent stages

• Stage 1 0.5 hr - 1 day

• Stage 2 1-3 days

• Stage 3 3-4 days

• Stage 4 4 days – 2 wks

Stage 1

• nausea, vomiting, diaphoresis, pallor, lethargy, and malaise.

• Some patients remain asymptomatic.

• Laboratory studies are typically normal.

• Such symptoms in acetaminophen-poisoned patients are usually due to coingestants ..

Stage 2

• the clinical and laboratory evidence of hepatotoxicity and, occasionally, nephrotoxicity become evident.

• Initially, stage I symptoms usually resolve and patients appear to improve clinically while subclinical elevations of hepatic aminotransferases (AST, ALT) occur.

• As stage II progresses, patients develop right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT) and total bilirubin, oliguria, and renal function abnormalities may become evident.

Stage 3

• Liver function abnormalities peak from 72 to 96 hours after ingestion.

• The systemic symptoms of stage I reappear in conjunction with jaundice, confusion (hepatic encephalopathy),

• Acute renal failure occurs in 25 percent of patients with significant hepatotoxicity and in more than 50 percent of those with frank hepatic failure

• Acute renal failure is due primarily to acute tubular necrosis.

• Death most commonly occurs in this stage, usually from multiorgan system failure..

Stage 4

•  Patients who survive stage III enter a recovery phase that usually begins by day four and is complete by seven days after overdose

• Histologic recovery lags behind clinical recovery and may take up to three months.

• When recovery occurs, it is complete; chronic hepatic dysfunction is not a sequela of acetaminophen poisoning

Both the mother and the fetus are at risk for hepatotoxicity following

an overdose of acetaminophen because acetaminophen, but not

the conjugated metabolites, freely diffuses across the placenta.

Acetaminophen is classified as pregnancy risk factor B.

( no toxicity in animal studies , but no controlled studies on pregnant women was conducted )

Pregnancy/Lactation

Treatment

1. Gut decontamination

2. Elimination enhancement

3. Supportive measures

4. Antidotes

GUT DECONTAMINATION

Activated charcoal should be given within the first several hours of ingestion of acetaminophen.

Activated charcoal may reduce the serum level of acetaminophen even after absorption is complete.

An acceptable standard dose for adults is 1 gram/kg.

Emesis or activated charcoal therapy is useful if the patient presents within 1 to 2 hours of an acetaminophen overdose.

If presented more than 1 to 2 hours after overdose, it is unlikely that GIT decontamination will be useful.

Exchange transfusion has been used in neonates following acetaminophen ingestion by the mother shortly before birth.

The primary use of hemodialysis in overdoses of acetaminophen is for the treatment of renal failure.

Peritoneal dialysis is ineffective.

Hemoperfusion does not have a well-defined role in the treatment of acetaminophen overdose.

ELIMINATION ENHANCEMENT

Basline blood tests for hospitalized patients should include CBC, LFT, glucose, electrolytes, and creatinine. Repeat liver function tests daily for 3 days, then as indicated by the appearance of hepatic encephalopathy.

Early signs of hepatotoxicity include hypoglycemia and metabolic acidosis.

The severity of the liver function abnormality is not a reliable predictor of outcome.

SUPPORTIVE MEASURES:

The prothrombin time is the best laboratory guide to the severity of hepatic encephalopathy.

Administer vitamin K1 for elevated prothrombin time (1.5x normal). Fresh frozen plasma should be used for severe prolongation (3x normal).

Repeat acetaminophen levels are unnecessary once serial levels indicate that peak levels have occurred and the last level is below the toxic line.

Maintain normal hydration and electrolyte balance and avoid forced diuresis.

Regular lactulose and enemas assist the elimination of nitrogenous substances and endotoxins from the bowel in encephalopathic patients.

Cerebral edema is a major cause of death following the development of hepatic encephalopathy and may be treated with mannitol and fluid restriction.

Antidotes

  N-ACETYLCYSTEINE “ NAC “

NAC is the N-acetyl derivative of L-cysteine.

It helps replenish diminished glutathione stores in acetaminophen overdoses.

Oral ( mostly ) and intravenous ( rarely ).

NAC provides maximum protection against hepatotoxicity when administered within 8 to 12 hours of an acetaminophen overdose.

NAC dosing is not based on acetaminophen blood levels.

NAC administration would appear justified in the presence of hepatotoxicity caused by acetaminophen, no matter what the time course or interval since the last dose.

Once NAC therapy begins, a full course of NAC should be administered regardless of the location of subsequent levels of acetaminophen on this nomogram.

METHIONINE

Methionine is an oral antidote used in Great Britain. Evidence in the United States has not been sufficient for adequate evaluation of its safety or efficacy.

Methionine acts as a glutathione precursor and protects against acetaminophen-induced hepatic and renal toxicity if it is administered within 8 to 10 hours of overdose.

CIMETIDINE

Cimetidine reduces acetaminophen-induced liver toxicity in animal models, but the amount of cimetidine required to inhibit the formation of toxic metabolites substantially following an overdose of acetaminophen probably is beyond a clinically acceptable dose. The role of cimetidine as adjunctive therapy to NAC is unproved.

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