What else does erectile dysfunction medication help with?

Why Viagra can impair vision and hearing, why it is prescribed to newborns, why it is tested on women, how it helped hamsters get the Shnobel prize, and how nitric oxide is involved in erections

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 causes can cause erectile dysfunction (the term “impotence”, which it is often called, has already outlived its usefulness in the medical environment). Curiously, the most famous drug for this condition was created for a completely different purpose.

The cure for hypertension comes from a Sandwich

Such a description could be guessed at the drug sildenafil, sold today under the brand name Viagra, as well as VIVASAN, sildenafil, Visarsin, Dynamico, Maxigra, Potenzagra and Revazio. The drug was developed in 1989 by employees of the Pfizer laboratory in Sandwich (this small town in the British County of Kent was originally called Sondwic, which comes from the words “sand” and “place to trade”, so now it is more correctly translated as “Soundwidge”, and not as the name of a sandwich). 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 did not come true: clinical studies have shown that sildenafil has almost no power over the heart’s 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 the idea came up to re-qualify 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 (by the way, the patent will expire in 2019, so Pfizer was 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 (food and Drug Administration, or FDA), and 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 to fight erectile dysfunction. This was much more convenient than injecting medicine with vacuum pumps, inserting suppositories (“candles”) into the urethra, sewing up capsules with it surgically, using injections, and even more so making implants. How was the new substance so different from the previous drugs in this group?

What does sildenafil consist of?

Sildenafil molecule structure

The level of the drug in the blood reaches between 30 and 120 minutes after administration. 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 varieties of them, which differ slightly in structure and “habitat”, but they all work on the same chemical reaction – they destroy the phosphodiester bonds that the same cGMP, or cyclic guanosine monophosphate, has. As you might guess, they were named for this, because in English these connections will be phosphodiester bonds, and the suffix “Aza” can boast a lot of enzymes.

Cyclic guanosine monophosphate regulates the conductivity of channels in cell membranes through which charged particles (ions) move out and in. Changes in charge on different sides of the membrane help transmit electrical signals, without which the work of nerve and muscle cells is unthinkable. For example, when phosphodiesterase 5 (PDE 5) is activated in response 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.

Phosphodiesterase

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, and are produced in receptors that respond to smell. But you can’t just slow down their splitting everywhere: we want to achieve an erection, but not to damage the retina, not to become deaf and not to faint from a critically low 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 do almost nothing else). As fashionistas like Chanel fragrances, 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 PDE 5 ten times more than PDE 6, 80 times more than PDE 1, and 700 times more than the others (for example, PDE 4, which is targeted by drotaverine as part of No-shpa – we have already written about it).

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 sildenafil’s “preference list”, 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 toxic damage to the retina, and the cones that are responsible for the perception of colors were most affected.

There is PDE 5 in the lungs, so another frequent use of sildenafil is the treatment of pulmonary hypertension. However, with fetal development disorders in the early stages of pregnancy, attempts to improve blood flow with this drug only harm unborn patients. The risk for them was shown by a study By the University of Amsterdam medical center, which had to be completed prematurely due to 11 cases of fetal death (for 93 subjects).

Stop ED

But as control of the blood flow of small pelvis is directly linked with the male erection? The inner lining of the vessels, or endothelium, is sensitive to changes in the level of nitric oxide II, or NO (no, the title was not a denial of caps), which is considered a gaseous signaling substance in the body. In the blood, it “lives” only a few seconds, but this time is enough to lead to the production of cGMP and command the walls of blood vessels to relax smooth muscles. they expand, and because of this, the pressure decreases-as will happen if you drive the same amount of liquid with the same force into wider pipes.

Take a deep breath, all this is summarized in the diagram below: in response to a sexual stimulus, endothelial cells and non-adrenergic non-cholinergic neurons release nitric oxide, which increases the work of an enzyme called guanylate cyclase. The latter converts GTP (one of the energy-carrying molecules in the cell) into cGMP, which relaxes smooth muscles, causing an erection. But this process also has a deterrent mechanism: phosphodiesterase 5 breaks the phosphodiester bonds of cGMP, turning it into GMF. Sildenafil in the form of citrate interferes with phosphodiesterase, helping the erection in place, although not getting to the cause, which may lie floors above this scheme. For example, if a patient with erectile dysfunction has nocturnal erections, the problem probably lies in the psychological plane.

Viagra and women

In a female homologous (having the same origin) organ – the clitoris – when aroused, an erection occurs by the same biochemical mechanism. Only here the blood is also filled with adjacent structures, the so-called bulbs of the vestibule (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. However, in parallel with the constant attempts to create a “female Viagra” in the form of tablets or substances for application to the vagina, ordinary Viagra was also repeatedly tested on representatives of the other half of humanity.

Not just for erectile dysfunction

Viagra can really be considered an effective remedy for erectile dysfunction caused by various causes (including unknown ones). The effect of the drug is confirmed by the patients themselves in specialized medical questionnaires, and direct measurements. The drug copes with erectile dysfunction in diabetes, and possibly in multiple sclerosis (although in the second case it is better to wait for the results of other studies). There is hope for patients with depression or those affected by the side effects of antidepressants.

But this is not the only purpose for which Viagra should be used. It is effective for arterial pulmonary hypertension and may even help newborns if the usual method of treatment is not available. But it is dangerous for pregnant women to take it: there is a risk of fetal development disorders.

A combination of Viagra and flu vaccine is being tested against metastases after removal of a cancerous tumor in the abdominal cavity. The results in mice are impressive: sildenafil does not allow PDE5 to prevent immune cells from attacking the intruder, and metastases cannot spread. However, even with successful trials, we will have to wait at least several years for this method to come into clinical practice.

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