Viagra – A magic blue pill discovered by chance

Prospective drugs are doomed to fail if the first human tests prove ineffective; they are even less likely to succeed if unanticipated side effects change the patient’s quality of life. This has been the story of thousands of drug candidates – Viagra (Sildenafil citrate) among them.

A unique combination of pharmacology instead rocketed Pfizer’s Viagra both into the cultural spotlight and medical success.

Sildenafil citrate was originally developed to combat high blood pressure and angina – both are conditions in which blood flow is restricted by narrow vessels. By inhibiting an enzyme that constricts blood flow, the original inventors hoped that this new drug would relieve chest pain and prevent future cardiovascular events.

The first tests in humans were disappointing, there was no observed effect in preventing or relieving the symptoms of heart disease. It was later discovered that the enzyme inhibited by Viagra is not present in the heart ventricles. It therefore had no effect for heart disease patients.

Instead, Dr. Nick Terrett, considered the father of Viagra, noted that male patients seemed especially keen to re-enroll in clinical trials – they reported an increased frequency of erections, and were hesitant to stop taking the drug.

It’s a long shot from relieving heart disease symptoms to prolonging male (and female) sexual arousal.

To understand this long shot, Pfizer had to look at where Viagra was working.

Muscle comes in three types – skeletal, smooth, and cardiac. Skeletal muscles are the ones we use during weightlifting or typing, they are under our control. On the other hand, cardiac and smooth muscle expand and contract without our input, thereby keeping us alive. These two types are found in the heart, surrounding blood vessels, the digestive tract, and the reproductive organs.

Since we don’t actively control smooth or cardiac muscle, they have evolved methods of controlling themselves. In the muscle surrounding blood vessels, expansion or contraction is controlled by the release of nitrous oxide (NOS – the compound used in laughing gas).

Nitrous oxide absorbed by muscle creates a new compound called cGMP, which is responsible for expanding blood vessels. Feedback signals eventually cause the smooth muscle to degrade cGMP, leading to contraction of the blood vessels.

This is where Viagra steps in. Some smooth muscles use an enzyme called PDE5 to degrade cGMP and cause blood vessel constriction. Viagra specifically inhibits PDE5 from working. Whereas Pfizer had hoped PDE5 was in the heart, it was instead found in the corpus cavernosum and the retina.

So, while Viagra can cause rare vision loss by affecting the retina, male patients were quick to forgive this minor side effect in favor of treating erectile dysfunction.

Since its extreme commercial success following release in 1998, more and more additional “side effects” have been added to the list of diseases treatable with Viagra. In 2005, it was approved to treat pulmonary arterial hypertension. Preliminary exercise science studies also seemed to demonstrate improved athletic performance for people on Viagra. Increased athletic performance was attributed to additional blood flow, however these results have been hotly debated since.

Since, people have been using it to cure things like altitude sickness, or even to preserve cut flowers (By preserving rigidity, ironically). It will be interesting to see what other disease indications it is discovered for in the future.

Moral of the story, scientists don’t always know what they are looking for, and your future prescription might be doing more than you had anticipated.

Image: The extremely recognizable “little blue pill”, marked with Pfizer on the front, and the dosage on the back.

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