Sildenafil in the treatment of erectile dysfunction

Erectile dysfunction (ED) is an erectile dysfunction in which the volume of a man’s penis, its firmness and straightness are insufficient for intercourse. Despite the fact that ED is not a serious health disorder, it can significantly worsen a man’s mental status, significantly reducing his quality of life, and hinder the realization of reproductive function. The data obtained in a large multicenter study of 16,370 men from 29 countries of the world (The Global Study of Sexual Attitudes and Behaviors) indicate that among men over 40 years old (the average age of the respondents is 55 years old), ED occurs on average with frequency of 10% (fluctuations from 8 to 22% depending on the region).

Scientists conducted an epidemiological study of the prevalence of ED in the United States among men aged 20–75 years. When analyzing the results of the survey using ICEF-5, it was revealed that only 10.1% of the men surveyed had no signs of ED, while a mild degree of ED was noted in 71.3%, an average degree of ED – in 6.6%, and severe degree – in 12% of respondents. Thus, out of 1225 men surveyed, the symptoms of ED were present in 1101 respondents. Of the 1,225 men, 115 responded that they had stopped having sex, and 69.6% of them cited ED as the reason for the termination.

Also, doctors received other data, according to which the prevalence of ED in men in the United States is 31.1%, while incomplete ED occurs in 17% and complete ED in 14.1% of men. ED in men aged 40–49 years occurs 2 times more often than in men younger than 30 years old, and at the age of 50–59 years old and 60–69 years old – almost 3 and 4.5 times more often, respectively. In men over 70 years of age, ED is observed in all cases.

In the United States, the results of a survey of a survey of 1225 respondents without a burdened urological history showed that only 10.1% of men surveyed had no signs of ED, while a mild degree of ED was noted in 71.3%, an average degree of ED was noted in 6.6%, and severe degree – in 12% of respondents. In terms of age composition, 28.3% of men reporting symptoms of ED were under 45 years of age.
A number of researchers involved in the correction of erectile dysfunction have identified the development of a therapy with the following ideal characteristics as the ultimate goal of research: simplicity, non-invasiveness, painlessness, high clinical efficacy, maximum naturalness of the drug action – the implementation of an action in response to natural sexual stimulation and the presence of mild adverse reactions.

Until the mid-1990s. ED treatment was a difficult task and in fact in most cases was reduced to the appointment of low-effective aphrodisiacs, or to the use of intracavernous injections or phalloendoprosthetics. The creation in 1986 of a drug with the original name UK-92,480 (hereinafter sildenafil), a highly selective phosphodiesterase type 5 (PDE-5) inhibitor, was the result of a search for chemical agents aimed at PDE-5 that could potentially be used in the treatment of ischemic heart disease (IHD). The results of the first clinical trials were not so encouraging for coronary heart disease (short half-life of sildenafil, negative interaction with nitrates). However, the advent of sildenafil has made a breakthrough in the treatment of ED.

In 2010, sales of sildenafil in the United States were $ 117 million and global sales reached $ 2 billion.

To determine the place of PDE-5 inhibitors in the treatment of ED, it is necessary to refer to the current recommendations for the treatment of ED and premature ejaculation (Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation, EAU, 2013).

According to these guidelines, the first line of therapy for ED includes:

• PDE-5 inhibitors (sildenafil, tadalafil, vardenafil);
• treatment with vacuum devices;
• shock wave therapy.

The second line of therapy (if the first line therapy is ineffective) includes drugs for intracavernous or endourethral administration: alprostadil or combined administration of various drugs.

In case of severe ED and ineffectiveness of the first and second line drugs, a radical surgical method is indicated – falloprosthetics.

In 2013, the European Urological Association formulated an algorithm for the treatment of ED, in which PDE5 inhibitors play a central role.

It must be understood that any of the PDE-5 inhibitors is not a drug that directly induces the formation of an erection. A signal metabolite, cyclic guanosine monophosphate (GMP), is involved in the mechanism of erection. The flaccid state of the penis is provided by constant sympathetic impulses, which maintains the tonic contraction of smooth muscle cells of trabeculae and arteries of the cavernous bodies of the penis, which limits the flow of arterial blood to the latter. Sexual stimulation causes suppression of the sympathetic and a sharp increase in parasympathetic impulses, accompanied by the release of nitric oxide by parasympathetic nerve endings. Nitric oxide enters the cell through the plasma membrane and interacts with guanylate cyclase, activating it. The activated cytoplasmic enzyme increases the formation of cyclic GMP (cGMP), thereby facilitating the leakage of Ca2 + ions from the smooth muscle cells of the corpora cavernosa. This leads to relaxation of smooth muscles, increases blood flow to the corpora cavernosa.

Among the PDE-5 inhibitors on the American pharmaceutical market, the following are present: sildenafil (Tornetis®, Kamagra®), vardenafil, tadalafil and udenafil. However, it must be recognized that sildenafil is the longest used and best studied.

Sildenafil was developed as a selective inhibitor of the activity of the enzyme PDE-5, which inactivates cGMP. Sildenafil increases the concentration of cGMP in the smooth muscle cells of the corpora cavernosa of the penis, which leads to their relaxation. Inhibition of PDE-5 in the smooth muscle cells of the corpora cavernosa leads to an increase in the concentration of cGMP by at least 50%.
Currently, 11 types of PDE are described (Table 1) (they, in turn, are subdivided into 21 subtypes). PDE isozymes play an important role in the contraction of smooth and striated muscles, regulation of vascular tone, the function of endocrine and other organs.

In comparable studies, an improvement in the ability to achieve an erection during therapy with sildenafil was noted by 84% of patients, during therapy with vardenafil – 80%, during therapy with tadalafil – 81%.

It is generally known that all PDE-5 inhibitors have a satisfactory safety profile, and as for the spectrum of side effects, it is characterized by both similar features and a number of differences.

It is necessary to emphasize that in a number of cases the indicated side effects occurred once, and did not occur systematically. In addition, placebo-treated patients experienced the same spectrum of side effects with the exception of color impairment. The most common side effects (headache, flushing, dyspepsia) are easily tolerated and do not require any additional therapeutic measures. In the event of side effects, their duration is determined by the duration of the drug’s action. So, after taking sildenafil, side effects persisted on average 3.9 hours, after taking vardenafil – on average 7.7 hours, and after using tadalafil – on average 14.9 hours. The percentage of drug withdrawals due to complications is comparable to that of placebo.

The development of side effects is associated with the inhibition of PDE-5 in different parts of the cardiovascular system, as well as with the fact that PDE-5 inhibitors do not possess unique superselectivity towards only PDE-5 and are able to suppress the activity of other isoforms, primarily PDE- 1, PDE-6, PDE-11. This leads to the accumulation of cGMP not only in the corpora cavernosa of the penis, but also in other organs. This is the reason for the appearance of certain side effects of PDE-5 inhibitors. Cyclic GMP realizes its action in a wide variety of signaling pathways, acting as an activator of protein kinases, which is the cause of various side effects associated with oversaturation of cGMP in various organs.

In the course of preclinical studies, it was established that sildenafil has a selectivity for PDE-5, which is 6-10 times higher than that for other isoenzymes. The selectivity of PDE-5 inhibitors in relation to other PDE subtypes from the point of view of safety of use and the profile of side effects is a very important property. Thus, the extremely low selectivity of sildenafil to PDE-11 determines its maximum safety in relation to the heart, pituitary gland and gonads compared to other representatives of this group. In addition, sildenafil has a selectivity for PDE-5, 6 times higher than that for PDE-6 found in the retinal tissues. PDE-6 plays an essential role in phototransduction, the process by which photons of light are absorbed and converted into electrical signals for transmission to the visual centers of the brain.

The spectrum of visual side effects, as a rule, is reduced to disturbances in color perception (the appearance of a bluish tinge), blurred vision and increased sensitivity to light. It was found that these side effects are rare (3%) when using low clinical doses (25 and 50 mg), more often (11%) when using high clinical doses (100 mg), and often (50%) when using 200 mg or more. At the same time, many researchers indicate that sildenafil does not affect visual acuity. Thus, in controlled clinical trials, it was found that doses up to 200 mg of sildenafil have no effect on visual acuity, visual fields, spatial contrast sensitivity and pupil response.

As for the effect of sildenafil on the cardiovascular system,  sildenafil is unlikely to be able to directly or indirectly influence myocardial contractility – neither the PDE-5 protein nor the PDE-5 messenger RNA were found in cardiac myocytes. And although the suppression of PDE-3 selective inhibitors leads to an increase in the inotropic function of the heart, nevertheless, sildenafil in therapeutic doses has no effect on it. In addition, the affinity of sildenafil for PDE-3 is 4000 times less than the affinity for PDE-5.

At the same time, sildenafil has a moderate vasodilating and antiplatelet effect due to the presence of PDE-5 in vascular smooth muscle and platelets. It is these effects that cause headaches, hot flashes and nasal congestion.

It is generally accepted that the efficacy and tolerability of PDE5 inhibitors cannot be assessed on the basis of a single dose of the drug. The patient should make several attempts and bring the dosage to the maximum recommended. In addition, titration of the dose of sildenafil can reduce the frequency and severity of major side effects. However, this does not mean that it is possible to take excessive doses of the drug, since exceeding the maximum dosage does not lead to an increase in effectiveness, but becomes the cause of a dose-dependent increase in side effects.

The fact that the side effects that develop when taking sildenafil are dose-dependent is indicated by a number of authors.

Taking this fact into account, it seems interesting to meta-analysis of the results of clinical studies carried out by R.A. Moore et al. According to the results of the study, the authors came to the conclusion that in the course of treatment with sildenafil, 50% of men who took 100 mg of the drug noted side effects of varying severity (headache, facial redness, change in color perception). Dose optimization (selection of the minimum effective dosage for each individual patient) allows you to keep the effectiveness at the same level and reduce the number of side effects by 41%.

In 2013, in addition to the original sildenafil, Tornetis®, manufactured by Sandoz, entered the American pharmaceutical market. The bioequivalence of Tornetis® to the original sildenafil was demonstrated in a comparative single-dose, randomized, double-crossover study by G. Morelli et al. in 2007. The authors of the study proved that in terms of the rate and volume of absorption when used on an empty stomach, there are no significant differences between Tornetis® and the original sildenafil. At the same time, unlike sildenafil, Tornetis® is a divisible tablet: if necessary, 100 mg of the drug can be easily divided into 4 equal parts. Thus, it becomes possible for the patient to choose any of the 3 dosages of the drug: 25, 50 or 100 mg, which allows the lowest effective dose to be used.