Viagra began life in a Pfizer search for a chest-pain drug
In 1989 Pfizer chemists were hunting for a treatment for angina, the chest pain of a starved heart. The compound they found, sildenafil, went on to become Viagra, approved in 1998. It works by relaxing blood vessels, which is also why it now treats a lung condition and can briefly tint the world blue.
Sildenafil blocks an enzyme called phosphodiesterase 5, or PDE5, which normally breaks down a signalling molecule, cGMP. When nitric oxide is released in response to arousal, cGMP levels rise and smooth muscle in blood vessel walls relaxes, letting blood flow in. By shielding cGMP from breakdown, the drug amplifies that response. Its shape resembles cGMP closely enough to compete for the enzyme. Crucially, it does nothing on its own without arousal. The underlying nitric oxide pathway earned Robert Furchgott, Ferid Murad and Louis Ignarro the 1998 Nobel Prize in Physiology or Medicine, the same year the drug was approved in the United States and the European Union.
The vessel-widening effect reaches the lungs, which is why sildenafil is also used for pulmonary arterial hypertension, though it improves disease markers without appearing to change the risk of death. It is sometimes used off-label for severe secondary Raynaud's phenomenon, with moderate benefit. Taken by mouth it typically acts within about twenty minutes and lasts around two hours; a high-fat meal slows absorption by roughly an hour.
Its quirks reveal its chemistry. The drug is selective for PDE5 but has some pull on PDE6, the version in the retina, so some users report cyanopsia, a blue tint to their vision. Headache, flushing and indigestion are common. Rare serious effects include sudden hearing loss, which prompted a more prominent FDA warning in 2007. Combining it with nitrate drugs such as nitroglycerin can cause a dangerous fall in blood pressure. The liver clears it mainly via the CYP3A4 enzyme, so some HIV medicines sharply raise its levels.
Popularity has brought odd side stories. Limited studies suggest it has little effect in people without erectile problems, despite recreational use. Unapproved analogues have been found hidden in so-called herbal aphrodisiacs, and when the FDA bans such products, sellers often just rename them. It is now a generic, sold in UK pharmacies without a prescription, and in 2023 ranked 151st among American prescriptions, with more than 3 million.
Source: Sildenafil
