The practice of medicine is full of mysteries. No one knows why otherwise healthy people get pancreatic cancer and some why life-long smokers live well into old age. Even though your doctor may not know why you have fibromyalgia (whole body pain with no apparent cause), you should at least know how your prescription for Gabapentin helps treat your pain symptoms (Gabapentin is a gamma-aminobutyric acid (GABA) agonist. GABA agonists reduce the excitability of neurons, including the pain neurons that travel from your body to your brain. If the pain neurons cannot get excited, they cannot transmit messages to your brain, resulting in reduced pain). It is curious that more people probably know how an internal combustion engine works than know why Pepto-bismol makes their tummy feel better. Medication should not be ingested simply on the faith that it will heal. A basic understanding of how medicine works is important for taking full advantage of these mini chemical powerhouses that can kill bacteria, reduce heartburn, prevent heart attacks, and heal sore muscles. Your medicine should never be a mystery.
    So let us start with one of the most common medications in the world, a drug taken at some point by 99.99% of the people reading this. It is a first line therapy for general practitioners seeing patients, mothers with sick children, and aging athletes after Sunday softball. Available in prescription and over the counter, found in households around the world, part of the World Health Organizations "List of Essential Medications"[1], and on the short list of most consumed drugs - alongside alcohol and caffeine - aspirin is the infantry of the pharmaceutical world.
    The story of this powerhouse drug begins, as most medical stories do, with Hippocrates when he told expectant mothers to drink the juice of freshly squeezed willow bark to make child birth more bearable. It would (much) later be found that willow bark contains salicin, a molecule that when consumed is converted to salicylic acid - a metabolite aspirin. Over the next couple of thousand years, most likely through a system of trial and error, willow bark extract was found to treat a variety of conditions including inflammation and fever [2]. It was not until the mid 19^th century that the active ingredient of willow bark was isolated, and soon after salicylic acid was being chemically synthesized. While the drug worked relative wonders for its time, doctors also noticed an abundance of side effects.
    In an attempt to find a safer alternative, a chemist at Bayer rediscovered acetylsalicylic acid, a molecule synthesized 40 years earlier [3]. Unlike the serendipitous use of willow bark, the synthesis of acetylsalicyclic acid and its rediscovery came about through simple brute force testing.  Charles von Gerhardt synthesized the molecule by methodically adding various chemicals together to create acid anhydrides. Felix Hoffman rediscovered acetylsalicyclic acid by systematically testing all the molecules in the Bayer inventory. (I like this story because it gives hope to the average graduate student. While insight and eureka moments are nice, it turns out that brute force can also lead to thesis-worthy data). Armed with this discovery, Bayer introduced Aspirin in 1899 ("a" from acetyl and "spririn" for the German word for salicylic acid) and over a hundred years and a lot of money later, aspirin continues to be a best seller with a 120 billion aspirin tablets consumed each year [4].
    Though intriguing, the history does not get us any closer to understanding why aspirin makes our heads feel better and our fevers decline. So here is how it works. When the human body is under attack, it initiates an inflammation response. While this helps direct the immune system to the site of invasion, it also causes redness, swelling, tenderness, and a host of other effects. The molecules floating in the bloodstream responsible for all these problems are prostaglandins - lipid molecules that activate pain neurons, increase fluid movement into tissue, control body temperature and increase platelet aggregation. Just as it is easier to put out a campfire before it spreads into a forest fire, it is easier to attack the production of prostaglandins then to block the end effects of the prostaglandins individually.
    Enter the cyclooxygenases (COX-1, and COX-2), the little enzymes that are the root of all our pain. COX-1 and 2 synthesize prostaglandins from arachidonic acid. By preventing the COXes from producing prostaglandins, all the unwanted downstream action of these lipid molecules can be stopped.And that is what aspirin does; it irreversibly destroys the COX enzymes, preventing them from unleashing a flood of prostaglandins and all their negative effects into the blood stream. Without prostaglandins, pain neurons are not as easily excitable, fluid cannot shift from the blood stream into tissues, platelets do not aggregate as easily, and the body’s temperature control center- the hypothalamus- is not stimulated to increase the thermostat. As a result, pain decreases, swelling goes down, clots do not form (this is the blood thinning effect that is especially desirable to people who have had prior strokes and heart attacks), and core body temperature returns to normal. In the end, aspirin is no more than the police squad that goes after the mafia head instead of the lowly gang members in order to prevent the flood illegal drugs in town - and all the ills they bring.
    As a side note, prostaglandins also have good effects. One of which is producing the mucous that lines and protects your stomach from stomach acid. Even though aspirin is better than salicylic acid alone, prolong use can still cause gastrointestinal problems.
    For the chemistry aficionados I would also like to present the mechanism of action. Aspirin chemically attacks the COXes and irreversibly acetylates serine 530 of COX-1 and serine 516 of COX-2 [5]. This blocks the binding pocket of the active site, preventing the COX substrate (arachidonic acid) from entering the active site and converting to prostaglandin GH2, the first product in the prostaglandin synthesis pathway.
    While the types of disorders and ailments that aspirin is used for (29 at last count) can be complicated, I hope you see that the mechanism of treatment can be quite simple. By examining the way the treatment works, you can get a better sense from where your problems might be coming. So next time you take that Maalox for heart burn, remember to ask yourself "how does this make me feel better?"

References

[1] http://www.who.int/medicines/publications/essentialmedicines/en/
[2] Rainsford KD "History and Development of the Salicylates" Aspirin and the Salicylates. London Butterworth and Co. 1984 1-12
[3] Hersh, E "Over-the-counter analgesics and antipyretics: A critical assessment" Clinical therapeutics 22:5, 500-548, 2000
[4] Warner, T and Mitchell, J "Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?" PNAS 99:21, 13371-13373, 2002
[5] Awtry, E and Loscalzo, J. "Aspirin" Circulation 101:10, 1206-1218, 2000