We just learned about aspirin, so let’s touch  on another very popular drug, acetaminophen.   Acetaminophen was first produced in 1877 by Harmon  Northrop Morse at Johns Hopkins University. It   wasn’t tested clinically, however, until 1893,  when it was compared against another leading   analgesic of the time, phenacetin, by Joseph von  Mering.

Mering noted that phenacetin use could   lead to methemoglobinemia, a condition that limits  the transport of oxygen to cells in the body.   Because of this, phenacetin was only used  extensively until 1949, at which point   biochemists David Lester and Leon Greenberg  showed that not only does the body metabolize   phenacetin into acetaminophen, but also that  acetaminophen is just as effective as phenacetin,   does not cause methemoglobinemia, and is  not carcinogenic, whereas phenacetin is.

Consequently acetaminophen became widely used, and  now, it is one of the most used drugs in the US,   commonly combined with other active  ingredients in over 600 medicines.  Acetaminophen, more commonly  known by the brand name Tylenol,   and also paracetamol as it’s called outside  of the U.S.

is often classified with NSAIDs,   or nonsteroidal anti-inflammatory drugs. Although  it is prescribed as an antipyretic and analgesic,   it is not a true NSAID because it has little  to no anti-inflammatory activity. Acetaminophen   can reduce fever and increase the threshold  for painful stimuli, but unlike any NSAID,   acetaminophen only very weakly inhibits the  cyclooxygenase enzymes that produce prostaglandins   which lead to pain, fever, and inflammation.

Because of this, acetaminophen is not a suitable   substitute for NSAIDs in chronic inflammatory  conditions such as rheumatoid arthritis.  The mechanism by which acetaminophen produces  its effects are actually not well known. It has   been suggested that it can inhibit cyclooxygenase  enzymes more effectively in the brain and central   nervous system, leading to its antipyretic and  analgesic effects.

These sites have a lower   concentration of compounds called peroxides,  which are produced at sites of inflammation   and have been shown to affect how well  acetaminophen can inhibit cyclooxygenase enzymes.   Others have suggested that this drug could  actually inhibit a third cyclooxygenase enzyme,   COX-3.

Although humans possess the gene that  encodes this third COX enzyme, no studies have   demonstrated its expression or function in humans. The weak inhibition of cyclooxygenase enzymes   makes acetaminophen a good choice for pain and  fever relief with little of the blood thinning   or gastric effects that are common to other  NSAIDs. Acetaminophen is therefore prescribed in   children and certain adult populations, like  asthmatics, who may have bad reactions to aspirin.

Though acetaminophen use does not  produce the common NSAID side effects,   it can at high doses cause liver toxicity,  which is an inflammation of the liver.  Acetaminophen can be processed by the liver  to be removed from the body by two pathways.   Normally, acetaminophen is metabolized  in a process called conjugation,   where a drug or its metabolite are chemically  coupled to an additional molecule to increase   its solubility and ability to be removed from the  body. Within the levels of a safe dose, molecules

of sulfate or glucuronide are covalently bound  to acetaminophen in order for it to be excreted.  Too much acetaminophen, however, will overload  or saturate this pathway, causing excess drug   to be shunted to a pathway where it 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,   which must be conjugated to a molecule  called glutathione in order to be excreted.   High levels of acetaminophen overloading this  pathway can deplete stores of glutathione,   leaving the reactive NAPQI product to covalently  bind to and disrupt other proteins in the liver,   leading to potentially fatal liver dysfunction.

This risk is more significant in people who are   fasting or consuming alcohol. Malnutrition can  lead to the depletion of glutathione stores,   thus limiting the liver’s ability to protect  itself from the toxic NAPQI metabolite.   And consuming alcohol can strain the liver  as well as induce, or increase the amount of,   CYP-3A4 enzymes that generate NAPQI from  acetaminophen.

So with acetaminophen   covered, let’s move on to another of the  best-known drugs in the world, ibuprofen