Viagra (Sildenafil) And Its Chemistry

     Erectile dysfunction is a common problem faced by elderly men. According to a report, about 60% of men older than 60 and 70% of those in their 70s have trouble getting or maintaining erections, often because of diabetes, cardiovascular disease or prostate cancer treatment. Not all of them want treatment, of course. A large proportion of older men have lost sexual interest, don’t have a partner or have other illnesses that preclude sexual activity. Paula Span writes in The New York Times (July 31, 2015 issue) on a heading “Sex Never Dies, but a Medicare Option for Older Men Does”. Yes, it does. She also writes that Medicare (Government medical insurance in USA) stopped covering erection pumps from July 1, 2015 an indication, some experts say, that the sexual health of older adults is not taken seriously. These erection pump treatment option naturally pulls blood into the erectile tissues to help men maintain an erection without medication or invasive procedures. That is another aspect to be discussed. Here, I want to discuss about the medication suggested by experts for erectile dysfunction and its chemistry.

    Viagra (sildenafil) is a suggested medicine for the erectile dysfunction for men (also women) that relaxes muscles found in the walls of blood vessels and increases blood flow to particular areas of the body. It has been since long to treat erectile dysfunction (impotence) in men. Another brand of sildenafil is Revatio, which is used to treat pulmonary arterial hypertension and improve exercise capacity in men and women. The chemical formula of Viagra is C₂₂H₃₀N₆O₄S and its IUPAC name is 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate.

Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett originally discovered sildenafil as a treatment for various cardiovascular disorders. Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (Cialis) and vardenafil (Levitra). Beside the treatment of erectile dysfunction, sildenafil is also used in pulmonary hypertension. While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects as of now. Furthermore, it has also been used as antidepressant-associated sexual dysfunction. Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction. In addition, the altitude sickness problem has been solved surprisingly by it. Sildenafil appears to improve some risk factors for high-altitude pulmonary edema but it is unclear whether or not it affects the rate of the condition itself.

    There are few side effects due to the administration of this drug in human body. Common side effects include headaches and heartburn, as well as flushed skin. Caution is advised in those who have cardiovascular disease. Rare but serious side effects include prolonged erections, which can lead to damage to the penis, and sudden-onset hearing loss. Sildenafil should not be taken by people who take nitrates such as nitroglycerin (GTN), as this may result in a severe and potentially fatal drop in blood pressure. Let’s know how this drug acts on the targeted area.

Mode of Action

Schematic illustration adopted from Peter Volsky

  Robert F. Furchgott, Ferid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation. In their study, they found that Sildenafil (Viagra) protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. A corpus cavernosum is one of a pair of sponge-like regions of erectile tissue, which contain most of the blood in the penis during an erection. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. The helicine arteries of penis are arteries in the penis which are involved in the process of erection. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. 

   Sildenafil is best regarded as a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Various researches have shown that the molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).

      After its desired action, Sildenafil is broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4(major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafil's action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.