Aspirin and Acetaminophen Toxicity Quiz

Acute Intoxication with Analgesic Antipyretics (Salicylates and Acetaminophen)

• Salicylates (e.g., aspirin) and acetaminophen (e.g., paracetamol) are analgesic antipyretics.
• Aspirin is a non-steroidal anti-inflammatory drug (NSAID).
• Acetaminophen is an over-the-counter pain reliever and fever reducer.
• Accidental and suicidal poisonings are common for salicylates, with children being particularly vulnerable.

Learning Objectives

• Understand the pathophysiology of aspirin overdose.
• Master the clinical presentation of aspirin toxicity.
• Be aware of the antidote and its administration time for aspirin.
• Be aware of aspirin toxicity management.
• Understand the pathophysiology of acetaminophen overdose.
• Master the clinical presentation of acetaminophen toxicity.
• Be aware of the antidote and its administration time for acetaminophen.
• Understand acetaminophen drug levels and timing.
• Be aware of acetaminophen toxicity management.

Salicylates (Aspirin)

• Salicylates are common over-the-counter (OTC) drugs, including aspirin, amino salicylic acid, methyl salicylate, salicylic acid.
• Aspirin is used for inflammation, pain, and fever.
• Accidental toxicity is common among children due to mixed-dose preparations.
• Suicidal toxicity is common in adolescents and adults due to the availability and painless nature of ingestion.
• Homicidal toxicity is infrequent due to the bitter taste and large doses required.

Aspirin Toxicokinetics

• Aspirin is rapidly absorbed from the gastrointestinal tract (GI tract).
• Approximately two-thirds of a therapeutic dose is absorbed within an hour.
• Peak serum concentrations typically occur within 2 to 4 hours.
• Serum concentrations may remain elevated for over 12 hours after large ingestions.
• Aspirin is metabolized by hydrolysis into salicylic acid, which binds to albumin.
• A toxic dose of aspirin is 200 to 300 mg/kg. 500 mg/kg is potentially lethal.

Aspirin Toxicokinetics (Metabolism and Excretion)

• Salicylates are primarily metabolized in the liver.
• Conjugation with glycine forms salicyluric acid, and with glucuronic acid creates salicyl acyl and phenolic glucuronides.
• Metabolic pathways can become saturated in overdose, leading to a non-linear increase in plasma salicylate levels.
• Salicylates are primarily excreted by the kidneys, involving glomerular filtration and tubular secretion.
• Urine pH significantly affects salicylate excretion; alkalinization promotes excretion, while acidification prolongs toxicity.

Aspirin Pathophysiology

• Early effects include respiratory alkalosis due to stimulation of the medullary respiratory center, increasing its sensitivity to pH and carbon dioxide partial pressure (PCO2).
• Subsequently, the kidneys compensate through excretion of bicarbonate, sodium, and potassium, which can lead to metabolic acidosis.
• Prolonged high aspirin concentrations can depress the respiratory center.
• Other effects include oxidative phosphorylation disturbances, causing hyperthermia and hypoglycemia, especially with brain glucose decrease, even in the absence of hypoglycemia.
• Gastrointestinal effects such as nausea, vomiting, and gastritis can occur.
• Hematological effects, including inhibition of platelet aggregation and hypoprothrombinemia, are possible.
• Tinnitus and hearing problems, and severe dehydration with oliguria and tubular damage are other potential outcomes.
• Fluid and electrolyte abnormalities are common in salicylate toxicity. Decreased renal blood flow and its direct nephrotoxicity are involved as well as inappropriate antidiuretic hormone secretion. Patients have hyperpnea, vomiting, sweating, and fever. Water excretion is increased (dehydration). Cerebral edema can occur, and any sensorium alteration is a significant sign.

Grading of Salicylate Poisoning

• Mild: Primarily gastrointestinal (GIT) manifestations (e.g., nausea, vomiting, epigastric pain, tinnitus).
• Moderate: Hypotension, hypoglycemia, hyperthermia, tachycardia, metabolic acidosis with Kussmaul breathing (deep, rapid breathing), and subconjunctival hemorrhage are seen.
• Severe: CNS psychosis, convulsions, respiratory and pulmonary edema, cardiovascular (CVS) failure, and renal oliguria/failure.

Laboratory Investigations for Salicylate Toxicity

• Serum salicylate level (at least 6 hours after ingestion, and 2 hours after an additional sample is crucial. )
• Arterial blood gases (ABGs) for pH status
• Electrolytes
• Blood glucose
• Renal function
• Liver function
• Coagulation profile
• Chest X-ray and ECG

Management of Salicylate Toxicity

• Supportive treatment:
• Intravenous (IV) fluids (e.g., D5 with bicarbonate)
• Monitoring of serum pH to prevent systemic alkalosis
• Monitoring for indications of dialysis (comatose, severe acidosis or hypotension, renal/hepatic/pulmonary failure, and pulmonary edema)
• Decontamination: Gastric lavage up to 24 hours, multiple activated charcoal doses with cathartics.
• Enhancement of elimination: Alkalinization of urine with IV sodium bicarbonate to promote salicylate ion trapping in blood and renal tubules inhibiting reabsorption, and hemodialysis in severe cases.
• Symptomatic treatment: Electrolyte correction (potassium), Vitamin K for coagulopathy, and sodium bicarbonate for metabolic acidosis.

Acetaminophen (Paracetamol)

• Acetaminophen is commonly found as a single product or in combination medications.
• Poisoning is typically accidental, though suicidal attempts are also common.

Acetaminophen Toxicokinetics

• Rapidly absorbed with peak plasma concentrations within approximately 1 hour. Complete absorption within 4 hours.
• Metabolized in the liver by conjugation with glucuronic acid and sulfate.
• A small percentage (less than 5%) is oxidized to a highly toxic metabolite (NAPQI) by cytochrome P450 in the liver.
• NAPQI reacts with glutathione, depleting it, leading to centrilobular necrosis in an overdose, and renal injury.

Acetaminophen Pathophysiology

• Hepatic injury is the key feature, potentially progressing to acute liver failure.
• Initial stages may be asymptomatic followed by non-specific symptoms like nausea, vomiting, and malaise; and potentially progress to right upper quadrant pain or tenderness, vomiting, and jaundice.
• Stages include initial non-specific symptoms followed by more pronounced hepatic effects (stage II), potential progression to peak hepatotoxicity (stage III) and death or recovery (stage IV) depending on treatment efficacy and promptness.
• Symptoms during the different stages include various combinations and progress of liver injury, such as rising AST/ALT concentrations, metabolic acidosis, coagulopathy, hepatic encephalopathy.

Investigating Acetaminophen Toxicity

• Assess severity via the Rumack-Matthew nomogram, using measured serum acetaminophen levels 4, or more, hours after ingestion to predict the need for an antidote.
• Relevant tests include liver function tests (AST, ALT), bilirubin, coagulation profile, blood glucose, kidney function tests, acid-base status, and electrolytes.

Managing Acetaminophen Toxicity

• Supportive care (ABCs), is crucial.
• Gastric lavage and activated charcoal decontamination, and enhanced elimination (e.g., increased urine pH) as well as other supportive measures such as prothrombin time maintenance with fresh frozen plasma and vitamin K, blood glucose with IV glucose, and liver/renal supportive therapy.
• Administer N-acetylcysteine (NAC) as the antidote.
• The dose and timing of NAC are critical. This is a time-critical intervention that needs to be initiated promptly given the window of time for its efficacy in prevention of liver damage.