Acetaminophen History & Uses

• Acetaminophen is a popular drug, with the brand name Tylenol, and is known as paracetamol outside of the U.S.
• Acetaminophen was first produced in 1877 by Harmon Northrop Morse at Johns Hopkins University, but not clinically tested until 1893.
• Joseph von Mering compared acetaminophen against phenacetin, a leading analgesic, and noted that phenacetin could cause methemoglobinemia, which limits oxygen transport to cells.
• Phenacetin was extensively used until 1949.
• Biochemists David Lester and Leon Greenberg showed that the body metabolizes phenacetin into acetaminophen.
• Acetaminophen is as effective as phenacetin, does not cause methemoglobinemia, and is not carcinogenic, unlike phenacetin.
• Acetaminophen became widely used and is in over 600 medicines in the US.

Acetaminophen vs. NSAIDs

• Acetaminophen is classified with NSAIDs (nonsteroidal anti-inflammatory drugs) but is not a true NSAID.
• Acetaminophen is prescribed as an antipyretic and analgesic, but has little to no anti-inflammatory activity.
• Acetaminophen reduces fever, increases the threshold for painful stimuli, but only weakly inhibits cyclooxygenase enzymes.
• Cyclooxygenase enzymes produce prostaglandins, which lead to pain, fever, and inflammation.
• Acetaminophen is not a suitable substitute for NSAIDs in chronic inflammatory conditions like rheumatoid arthritis.

Mechanism of Action

• The mechanism of action for acetaminophen is not well-known.
• Acetaminophen may inhibit cyclooxygenase enzymes more effectively in the brain and central nervous system, leading to antipyretic and analgesic effects.
• These sites have lower concentrations of peroxides, which affect acetaminophen's ability to inhibit cyclooxygenase enzymes.
• Others suggest that acetaminophen could inhibit a third cyclooxygenase enzyme, COX-3, but no studies have demonstrated its expression or function in humans.
• Weak inhibition of cyclooxygenase enzymes makes acetaminophen a good choice for pain and fever relief.
• Acetaminophen has little of the blood thinning or gastric effects common to other NSAIDs.
• Acetaminophen is prescribed in children and adult populations, like asthmatics, who may have bad reactions to aspirin.

Liver Toxicity

• Acetaminophen use does not produce the common NSAID side effects, but at high doses can cause liver toxicity, an inflammation of the liver.
• Acetaminophen is processed by the liver to be removed from the body via two pathways.
• Normally, acetaminophen is metabolized via conjugation, where it is chemically coupled to another molecule to increase solubility for excretion.
• Within safe dose levels, sulfate or glucuronide molecules are covalently bound to acetaminophen for excretion.
• Too much acetaminophen can overload the conjugation pathway.
• Excess acetaminophen is metabolized via oxidation by the liver enzyme cytochrome-3A4, or CYP-3A4.
• Metabolism of acetaminophen by CYP-3A4 creates a toxic product called NAPQI.
• NAPQI must be conjugated to glutathione to be excreted.
• High levels of acetaminophen can deplete glutathione stores, leaving the reactive NAPQI to covalently bind to and disrupt proteins in the liver.
• This can lead to potentially fatal liver dysfunction.
• This risk is more significant in people who are fasting or consuming alcohol.
• Malnutrition can deplete glutathione stores, limiting the liver's ability to protect itself from NAPQI.
• Consuming alcohol can strain the liver and induce CYP-3A4 enzymes, which generate NAPQI from acetaminophen.