How The Little Blue Pill screws…your vision
A complete lifestyle overhaul can be notoriously difficult to maintain. Think about how long those “work out more” New Year’s resolutions last - ask a dedicated fitness fanatic about the surge in gym memberships in January, and the subsequent fall in February. Since a sedentary lifestyle and obesity are risk factors for heart disease, wouldn’t it be great if there was just a pill that could help improve heart health?
In the late 1980s, researchers from the pharmaceutical giant Pfizer were working on this exact question. They were interested in treating angina pectoris, the recurring shortness of breath and sensation of pain in the chest that is a known symptom of chronic heart disease. Usually, angina pectoris results from a decrease of blood flow to the heart itself. Since the leading cause of American deaths in the 1980s (as well as today) was cardiovascular disease, there was much demand for a drug that improves circulation through the blood vessels.
Pfizer had developed a promising compound called UK-92,480 that went to Phase I clinical trials for heart pain. However, the drug wasn’t as effective as predicted, and researchers were disappointed by the results. The drug remained in the body for such a short time, patients had to be given the pill three times a day to maintain a constant dose in the blood. Also, there were reports of some unpleasant side effects, like muscle aches. 1
As fate would have it, there was one very pleasant side effect: many male volunteers reported they were having more frequent erections.
The physiological premise behind this drug was to increase blood flow to the heart by dilating the blood vessels. The pharmacological target was a class of intracellular signaling molecules called cyclic nucleotides, such as cyclic GMP (cGMP). Increased levels of cGMP was known to produce vasodilation by relaxing the smooth muscles that regulate blood vessel diameter.
Outside of the circulatory system, cGMP has other functions in different cell types. For example, these molecules regulate the properties of ion channels in neurons, which changes their excitability properties. They are also important for cell growth and gene transcription. 2
The concentration of cGMP in a cell is a dynamic process. Enzymes called cyclases are responsible for building these molecules. At the same time, a competing process driven by enzymes called phosphodiesterases (PDEs) break them apart. At any given time, the concentration of cGMP is pulled in two directions, like a game of molecular tug-of-war.
As construction and destruction takes place simultaneously, changing the “strength” of one side causes a shift in the balance of cyclic molecules. For example, some neurotransmitter signals bump up the activity of the cyclases, which increase cGMP levels.
The other way to change this equation is to decrease the degradation process. A class of chemicals called PDE inhibitors block the breakdown of the cyclic nucleotides, resulting in an increased concentration of cGMP. The failed heart medication, as a PDE inhibitor, biases the balance towards higher cGMP levels.
https://openwetware.org/wiki/BIO254:2ndMessenger
There are more than 11 different subtypes of PDEs. Of critical importance, the different isoforms are found in different parts of the body. PDE 5, the specific subtype that the drug had the strongest affinity towards, is expressed in small amounts in the heart, which explains the mild clinical effect for treating angina. By stroke of luck, there is a lot of PDE 5 in the walls of the corpus cavernosum, the tissue of the penis that fills with blood during those special moments.
In 1998, when the FDA approved Pfizer’s PDE inhibitor as a sexual enhancement drug for the treatment of male impotence, sildenafil citrate (Viagra) joined the ranks of the many drugs that successfully pivoted to a completely different market from the original intent.
https://www.thedailybeast.com/he-took-35-viagra-pills-for-laughs-got-five-day-erection
As effective as The Little Blue Pill was for bedroom performance, no drug is without side effects. Some patients were reporting that their vision was tinted blue, a clinical sign called cyanopsia - as if their romantic partners became Avatar people. Thankfully, these vision changes were temporary, lasting only for a few hours. When the drug was metabolized out of the body, their partners un-Smurfed themselves. 3
As is the case with almost all compounds created in a lab, Viagra does not have great selectivity for its intended biological target, the PDE 5 enzyme. It has some capacity to inhibit a closely related isozyme, PDE 6. This isozyme is expressed heavily in the rod photoreceptor cells of the retina, the population of cells that contribute most to our scotopic vision, the vision system used in low-light conditions, such as at bedtime. These rod cells are most strongly activated by blue wavelengths of light, which is one reason why colorful stimuli at night appear more blue than red (this perceptual illusion is called the Purkinje shift.)
The function of these rod cells is heavily dependent on levels of cGMP. In the complete absence of light (imagine you are deep within a cave system with no sources of artificial light), intracellular levels of cGMP are high. These molecules bind to and activate cyclic nucleotide gated sodium channels, which allow for the movement of sodium ions into the cell. This sodium flux can be measured experimentally, and is called the “dark current”: it’s a movement of ions (current) that is strongest in the dark. The steady flow of positive charges into the rod cells leads to depolarization. In total darkness, rod cells may be as depolarized as -40 mV.
When one of these rod cells gets hit with photons of light, the phosphodiesterase enzymes increase in activity, which decreases the cGMP levels inside the cells. Less cGMP means smaller dark current, which causes the cell to hyperpolarize. This hyperpolarization is the beginning of a signaling pathway that gets passed into the brain, which then decodes that signal as light.
http://flipper.diff.org/app/items/info/1385
When Viagra is present, it blocks the action of PDEs in these cells, thus elevating the concentration of cGMP. It is still unclear exactly how this increase in cGMP leads to Pablo Picasso vision. One theory suggests that the increased dark current causes the rods to be more sensitive (in more ways than one, if you get my drift) to changes in light levels, since there is now a greater degree of hyperpolarization possible when light strikes the photoreceptor. Since rods tend to peak their activity in the bluer range of wavelengths, their increased sensitivity causes our brain to register more blue signals than other colors.
At extremely high doses, PDE inhibitors are toxic to rod photoreceptors. One case report describes a patient who, against all medical advice and common sense, drank an entire bottle of liquid sildenafil, resulting in an overdose of about 10 times the typical dosage. He experienced three major symptoms, all congruent with rod-selective cell damage:
Night blindness. With the scotopic vision system damaged, he would have a difficult time seeing under low-light conditions.
A reddish tint to his vision. If increased sensitivity led to the perception of a bluish tint, then destruction of the cells that are sensitive to blue would lead to the opposite end of the color spectrum (reds) dominating his vision.
A donut-shaped deficit in his field of vision. Most rod photoreceptors are expressed in the periphery rather than in the center of our vision. 4
“Blu~~ue looks good on the skyLook good on that neon buzzing on the wall
But darlin it don’t match your eyes”
-Keith Urban
1 https://cosmosmagazine.com/science/biology/how-i-discovered-viagra/
2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838136/
3. https://link.springer.com/content/pdf/10.2165/00002018-200932010-00001.pdf
4. https://jamanetwork.com/journals/jamaophthalmology/article-abstract/2720488