Featured Poison

Salicylic Acid: The Journey From Humble Willow to Aspirin

Willow Tree by Geaugagrrl (released to public domain CC0)

Willow Tree by Geaugagrrl (released to public domain CC0)

Plant based medicines have been around nearly as long as humans, but one stands out more than all the others combined. The ancient Sumerians, circa 2000 BC, recorded the use of willow leaves to treat inflammation. The Ebers Papyrus, circa 1500 BC, one of the most important medical documents of ancient Egypt, references the use of willow leaves as a general purpose pain reliever. And Hippocrates himself advocated the use of willow bark tea to reduce fever and alleviate pain (1). Jumping ahead to modern times, the first ever recorded clinical trial was centered around willow bark, when in 1763 Reverend Edward Stone sought a treatment for the symptoms of malaria (2). In ground willow bark he found success, but it took nearly 100 years for science to unlock its secrets.

In 1828 German chemist and professor Joseph Buchner isolated yellow crystals from willow extract – on a Buchner funnel, perhaps? I have no idea if it was named after him, but I vote “yes” – and named the crystalline compound “salicin,” after the genus of the willow tree, Salix. Ten years later, in 1838, Raffaele Piria – who to my knowledge has nothing named after him – isolated a different, more potent, compound from willow, and called it salicylic acid. With only a name to go off of, salicin and salicylic acid found widespread use as a pain reliever and fever reducer. Things started to change in 1852 when Professor Gerhart, of Montpellier University, decoded the molecular formula of salicylic acid (2).

This discovery allowed for the synthesis of salicylic acid, rather than the production of it from salicin, and at a cost 10 times less. The use of cheap salicylic acid spread far and wide for the treatment of rheumatism, arthritis, and gout, at doses up to 6 grams per day. There is no such thing as a free lunch however, as salicylic acid has the rather severe side effect of GI irritation. The newly formed pharmaceutical wing (more of a closet in reality) of Friedrich Bayer & Company directed chemist Felix Hoffman, under the supervision of Arthur Eichengrun, to synthesize derivatives of salicylic acid (2). Their goal was to discover a derivative of salicylic acid that possessed anti-inflammatory properties, yet without the GI side effects – something that Hoffman’s father suffered from. The group succeeded by acetylating the phenol functional group, making acetylsalicylic acid, now known throughout the world as Aspirin.

Aspirin1

Note: History, and Bayer, have dictated that Hoffman was the inventor of Aspirin. However, documents from Eichengrun and some common sense suggests that he was the one who devised the plan for Aspirin, with Hoffman merely carrying out the synthesis. In pre-WWII Germany, during which time the Nazi party took control, Eichengrun, who was Jewish, no doubt felt pressured to stay silent so he could continue his work with little interference. In 1944, while in the Theresienstadt concentration camp at the age of 76, he typed his accounts of the discovery of Aspirin. Personally, I believe Eichengrun. For some helpful reading on the subject, see references 3, 4 and especially 5, for a fantastic tribute to a talented chemist.

Today, Aspirin is used annualy by nearly 100 million Americans to the tune of over 10,000 tons. Used primarily as a pain reliever, it also is used daily as an antiplatelet therapy to reduce the occurrence of cardiovascular disease and stroke, with daily doses around 80-160 mg/day (6). But while lifesaving, the cheap, over-the-counter drug also takes lives. In order to understand how, we need to know a bit about how Aspirin works.

Aspirin works by several mechanisms 1.)  as a prodrug – once absorbed through the gut the acetyl group is cleaved by esterases, resulting in . . . salicylic acid, and 2.) transferring the acetyl group to a cyclooxegenase enzyme, effectively disabling the enzyme in an irreversible manner.  The  prodrug technique is still widely used today to reduce side effects or increase circulating half-lives, as well as extend patent life for older drugs . . . I’m looking at you, Claritin. And the second mechanism is the one now believed to be most responsible for Aspirin’s actions, though it took about 75 years to decipher.

Bayer Aspirin from Bayer AG (CC BY-SA-3.0)

Bayer Aspirin from Bayer AG (CC BY-SA-3.0)

Cyclooxygenase (COX), of which there are two sub-types, COX-1 and COX-2, are enzymes needed to synthesize prostaglandin and thromboxane. Prostaglandins are chemicals that are important in the transmission of pain and inflammation. Thromboxanes are chemicals responsible for rounding up platelets and forming blood clots. As an irreversible inhibitor of COX-1, Aspirin supresses the production of prostoglandins and thromboxanes, so you don’t feel pain or inflammation when you hurt yourself, and your blood doesn’t clot up, which can help prevent heart attacks and strokes. Wait a minute . . . isn’t clotting important? Right you are. If you cut yourself, you’d like your body to help stop the bleeding, wouldn’t you? Thought so.

Additionally, the COX enzymes, via the prostoglandins, are responsible for the protective mucosal lining in the gut. Erosion of the mucosal lining leads to GI bleeds, which can be not only painful, but deadly. Even low-dose aspirin for the prevention of heart attacks and strokes contribute to GI bleeds (7). Including all the risks associated with Aspirin, and similar drugs, they account for over 16,000 deaths per year and 2 billion dollars in costs due to complications (8, I think the 16,000 is exaggerated, but deaths are still very high). Still, the reward of preventing an MI or stroke outweighs the risk of GI bleed, but that’s a discussion you need to have with your doctor, not me.

So the next time you reach for that bottle of Aspirin, think not only of its risks, but of the Sumerians and Egyptians, and the four thousand year journey it took to reach you.

References:

1. Mackowiak, P. A. “Brief History of Antipyretic Therapy.” Clinical Infectious Diseases 31.Supplement 5 (2000): S154-156.
2. Fuster, V., and J. M. Sweeny. “Aspirin: A Historical and Contemporary Therapeutic Overview.” Circulation 123.7 (2011): 768-78.
3. Sneader, W. “The Discovery of Aspirin: A Reappraisal.” Bmj 321.7276 (2000): 1591-594.
4. Rinsema, Thijs J. “One Hundred Years of Aspirin.” Medical History 43.04 (1999): 502-07.
5. Vaupel, Elisabeth. “Arthur Eichengrün—Tribute to a Forgotten Chemist, Entrepreneur, and German Jew.” Angewandte Chemie International Edition 44.22 (2005): 3344-355.
6. Dalen, James E. “Aspirin to Prevent Heart Attack and Stroke: What’s the Right Dose?” The American Journal of Medicine 119.3 (2006): 198-202.
7. Lanas, Angel. “Gastrointestinal Bleeding Associated with Low-dose Aspirin Use: Relevance and Management in Clinical Practice.” Expert Opinion on Drug Safety 10.1 (2011): 45-54.
8. Wolfe, M. Michael, David R. Lichtenstein, and Gurkirpal Singh. “Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs.” New England Journal of Medicine 340.24 (1999): 1888-899.

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11 thoughts on “Salicylic Acid: The Journey From Humble Willow to Aspirin

  1. Aspirin got it’s name from the salicin-rich herb Spirea ulmaria (Meadowsweet) … i.e., “a-spirea” (from spirea). Ironically, besides being used as an herbal analgesic, Meadowsweet has been used traditionally to treat irritation and inflammation of the GI tract, which is very different from the irritation of the GI tract caused by acetylsalicylic acid.

  2. 1. Ernst Büchner of the filtration fame was born in 1850, so it was not him.
    2. Aspirin is not a prodrug of salicylic acid, it is a reactive derivate of salicylic acid. Acetyl group in aspirin survives to a surprisingly high degree all the way from the gut to the bloodstream, and is the main reason aspirin is more potent than salicylic acid: The acetyl group in aspirin is delivered into the cyclooxygenase active site and transferred onto a serine residue hydroxyl in COX1 and 2, this is the mechanism of the irreversible inactivation of cyclooxygenases by aspirin. Whereas salicylic acid binding alone is a reversible inhibition.

    • Yeah, I didn’t think it would be the same Buchner.

      And yeah, inhibiting the upstream expression of the COX genes is the best explanation, but not the simplest for my audience. Aspirin is hydrolyzed rapidly in the gut, and free aspirin in the blood has a half-life of 20 minutes. Though given the 1:1 stoich of aspirin and acetylation, you probably don’t need much. You still can’t discount salicylic acid itself, working as a reversible inhibitor, especially at high aspirin doses. There are many similar NSAIDS that don’t acetylate. Perhaps I can do a “Master Class” on this later. Thanks!

  3. I once, rather smugly, thought I could treat my seborrhoeic dermatitis with cheap, generic, soluble asprin, smooshed up in water and applied topically. The “proper stuff” was bloody expensive, but it said its active ingredient was salicylic acid, so, same thing, right? Then I read a bit further on Wiki-who-needs-a-medical-degree-pedia, and learned about asprin being a pro-drug, so not the same thing after all…

    Then I read a bit more, and concluded that biochem is *hard*, yo. So, was I right, is there a plausible mechanism of action for soluble asprin in water, applied topically?

    Yes, I know about coal tar.

    I know I’m late commenting, I just discovered this blog today, and I’m loving it, my limitations notwithstanding. I’d rather read something a bit too hard than something a bit too easy.

  4. It’s never too late to comment.

    A lot of the ingredients in these topical formulations are for fluff, filler, and fragrance, but some actually help deliver drug through our hydrophobic skin and tissue. Water alone is not sufficient to deliver drug through these layers, so it’s not all marketing “make you smell good” crap.

    I appreciate you finding the site and reading!

  5. Pingback: Pennyroyal: Nature’s Herb or Abortifacient? | Nature's Poisons

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