Acetaminophen (Tylenol)

Fast Facts:

• Introduced in 1950, hepatotoxicity recognized in 1966
• Accounts for more overdoses and overdose-related deaths than any other drug. (~23%)
• Most common cause of acute liver failure in alcoholics
• Generally good outcome if N-acetyl cysteine is given

Effects and mechanism:

Has analgesic and antipyretic (fever-reducing) effects. The mechanism is not really known but it acts centrally to inhibit prostaglandin synthesis. Some theories say it might inhibit a third version of cyclo-oxygenase (COX-3) but that has not been proven. Its antipyretic effects are a result of its effect on the temperature regulating region of the hypothalamus.

Toxicity!

Normally, 90% of acetaminophen is conjugated to sulfate or glucuronide. This conjugate is then excreted in urine. 5% is excreted unchanged the remaining 5% is metabolized by the p450 to NAPQI. NAPQI is hepatotoxic (oxidative injury and necrosis) and is conjugated to glutathione and excreted.

Excess NAPQI occurs for these reasons:

• Excess acetaminophen intake overloads livers ability to conjugate to sulfate or glucuronide

• Decreased ability to glucuonidate or sulfate

• Induction of p450 enzymes (Occurs in chronic alcoholism)

• Depletion stores of glutathione (Chronic alcoholism)

Hepatoxicity

Hepatic injury is caused mainly when glutathione stores are depleted by 70%. To eliminate NAPQI, N-acetyl-cysteine is given which is a precursor to glutathione. With this new glutathione the NAPQI can be excreted.

Acetaminophen --> acetaminophen-glucuronide -->Acetaminophen-sulfate --->P450 Excretion ---> NAPQI --->NAPQI-glutathione

Category: Pharmacology Notes