Erectile Dysfunction

What they treat us with: Viagra

Neurological disorders, hormonal disorders, diseases of the cardiovascular system, surgery, diabetes, multiple sclerosis, taking certain medications, alcohol or drug intoxication and psychological problems-all these reasons can cause erectile dysfunction (the term “impotence”, which it is often called, has already outlived itself in the medical environment). It is curious that the most famous drug for this condition (Viagra) was created for a completely different purpose. We dedicate this article to him.

The cure for hypertension comes from a Sandwich

Under such a description, the drug sildenafil, sold today under the brand Viagra, as well as Kamagra, Silagra, Caverta, Fildena could be guessed. The drug was developed in 1989 by employees of the Pfizer laboratory in the city of Sandwich (this small town in the British county of Kent was originally called Sondwic, which came from the words “sand” and “a place to trade”). Scientists wanted to create a drug to improve blood flow in the myocardium in coronary heart disease and angina, as well as to combat high blood pressure (hypertension).

But their plans were not destined to come true: clinical studies have shown that sildenafil has almost no power over the cardiac blood flow. But then Pfizer employees remembered how in the first clinical trials they noticed a frequent side effect of the drug — spontaneous erections. So there was an idea to retrain the drug for the treatment of erectile dysfunction, and since it affects 31% of men aged 50-59 years, they attacked almost a gold mine.

In 1996, the drug was patented (the patent expired in 2019, so Pfizer played ahead of the curve and released its own generic, that is, a cheap copy of the drug). In 1998, the drug was approved by the American Food and Drug Administration (FDA), in the same year it was allowed in Europe. Sildenafil has become one of the most famous examples of repurposed medications and the first pill that can fight erectile dysfunction. It was much more convenient than injecting the medicine with vacuum pumps, inserting suppositories (“candles”) into the urethra, sewing capsules with it surgically, using injections and even more so making implants. How did the new substance differ so much from the previous drugs of this group?

Chemical composition of viagra

Chemical composition of viagra

The level of the drug in the blood reaches between 30 and 120 minutes after administration. Being absorbed by 40%, the drug is gradually destroyed by liver enzymes (mainly cytochrome P450 3A4, and to a lesser extent – cytochrome P450 2C9) and is excreted in the feces (80%) and urine. After 3-4 hours, half of the dosage already leaves the body.

Before that, it manages to play its main role – to block the action of enzymes called cGMP-specific phosphodiesterases. We have more than a dozen of their varieties, which differ slightly in structure and “habitats”, but they all work for the same chemical reaction – they destroy the phosphodiester bonds that the same cGMP, or cyclic guanosine monophosphate, has.

Cyclic guanosine monophosphate regulates the conductivity of channels in cell membranes, through which charged particles (ions) move outward and inward. Changes in the charge on different sides of the membrane help to transmit electrical signals, without which the work of nerve and muscle cells is unthinkable. For example, when phosphodiesterase 5 (PDE 5) is activated, reacting to light hitting the mammalian retina, it also destroys cGMP, which causes hyperpolarization of the membrane of light-sensitive cells, sending a signal from the eye to the brain.

Viagra: Phosphodiesterase No. 5

cGMP molecules work throughout the body: they cause blood vessels to expand, are present in platelets, indicate the direction of growth to short processes of pyramidal neurons, are produced in receptors that respond to smell. But we can’t just slow down their splitting everywhere: we want to achieve an erection, but not to damage the retina, not to go deaf and not to faint from critically lowered blood pressure. Therefore, a pill that blocks PDE should only work in certain parts of the body.

Fortunately, as we remember, there are many types of phosphodiesterases, and as many as 11 of them prefer to cut phosphodiester bonds in cGMP (and three of them are practically only doing this). As fashionistas like the fragrances of the Chanel brand, so cGMP-specific phosphodiesterases like sildenafil, but most of all, as in the case of famous perfumes, No. 5 is attractive to him. He likes the drug ten times more than PDE 6, 80 times more than PDE 1 and 700 times more than the others.

The fifth phosphodiesterase as a target for the treatment of erectile dysfunction is good because it is most produced in the cavernous bodies of the penis. In addition, there is a lot of it on the retina (no wonder we wrote about cGMP and vision). Phosphodiesterase 6, the second in the “list of preferences” of sildenafil, is also active there. Therefore, an overdose of Viagra can lead to color blindness – for example, one hero of an article in Retinal Cases began to see the world in red shades, because he received a toxic lesion of the retina, and the cones that are responsible for the perception of colors suffered the most.

Viagra and women

In a female homologous (having the same origin) organ-the clitoris – when aroused, an erection occurs according to the same biochemical mechanism. Only here the adjacent structures are also filled with blood, the so-called bulbi of vestibule, which men do not have (and women do not have a spongy body). They, like the female homologues of cavernous bodies, look like separate structures, but they also swell and become harder, filling with blood during arousal.

It is logical to assume that sildenafil will also work on women who have similar problems. But such disorders in women are much less obvious for diagnosis: even the 3D structure of the internal parts of the clitoris was mapped only at the beginning of the two thousandth. Nevertheless, in parallel with the constant attempts to create a “female Viagra” in the form of tablets or substances for application in the vagina, ordinary Viagra has also been tested more than once on representatives of the female half of humanity.

Although articles and reviews most often hint that PDE5 inhibitors may well help women, such studies are often sketchy and few in number. We know very little about the side effects in women, and in general, like in men, the problem may not be in the tricks of phosphodiesterase 5, but at another level. Therefore, it is better to listen to the advice of a review of scientists from the University of Ferrara, who recommend first diagnosing the primary cause of female sexual disorder (although it is difficult), so as not to miss a serious systemic disease, and only if other drugs do not help, try drugs of this group.

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