Sildenafil: side effects, contraindications

The review examines the epidemiology, etiology and pathogenesis of erectile dysfunction. The clinical effects of the most long-used drug for the treatment of erectile dysfunction, sildenafil, which is also a reference drug in comparative clinical studies of the effectiveness of phosphodiesterase type 5 inhibitors, are characterized. It is noted that taking sildenafil leads to an improvement in the condition of patients of different ages, regardless of the etiology, severity and timing of erectile dysfunction. Data on the safety of the drug sildenafil are provided. The prospects for long-term continuous use of the drug are discussed.

Introduction

Erectile dysfunction (ED) is a pressing problem in urology. This is due not only to the high prevalence of ED in the population, but also to a revision of views on the causes of ED, changes in therapeutic approaches, the study of the relationship between ED and symptoms of the lower urinary tract, the need to correct erectile dysfunction after various urological operations (radical prostatectomy, urethroplasty, transurethral endoscopic surgery) [1–3].

ED is defined as the permanent or temporary inability to achieve and maintain an erection sufficient for successful sexual intercourse. Despite the fact that ED is not life-threatening, the appearance of sexual disorders leads to rapid personal and social maladaptation of the patient. In addition, in some cases, ED may be the first symptom of serious diseases (diabetes mellitus, demyelinating diseases of the spinal cord).

According to classical population studies conducted in the 20th century, the prevalence of ED increases with age. In men over 21 years of age, the incidence of ED is 10%, and among men over 60 years of age this figure triples. In the most socially active category of men (40–70 years old), 50% suffer from ED. Moreover, the frequency of ED is approximately the same among representatives of all races and continents [4].

Description and main characteristics

Sildenafil is a drug used by men to increase potency. Contains the active ingredient of the same name and is available in the form of granules with different dosages of the main component - from 35 to 140.5 mg per 1 piece. The most well-known brand of the drug, which also contains sildenafil, is Viagra.

The product is dispensed from pharmacies only with a prescription. The shelf life is 3 years from the date of production. It must be stored under standard conditions - a dark place, temperature up to 25 degrees.

Modern view on the use of sildenafil citrate

Journal "Experimental and Clinical Urology" Issue No. 1 for 2015

Efremov E.A., Kasatonova E.V., Melnik Ya.I.

Erectile dysfunction (ED) is characterized by a persistent inability to achieve or maintain an erection sufficient for successful sexual intercourse. This erectile dysfunction is widespread and according to KK Chew et al. by 2025, it is estimated to affect 322 million men worldwide [1].

Data from the latest separate study on the prevalence of ED in 6 regions of the Russian Federation were obtained in 2012 based on an analysis of survey data from 1225 respondents. When analyzing the IIEF-5 questionnaire, it was revealed that only 10.1% of surveyed men had no signs of ED, while a mild degree of ED was noted in 71.3%, a moderate degree in 6.6% and a severe degree in 12 % of respondents. Thus, out of 1225 men surveyed, symptoms of ED were present in 1101 (89.9%) respondents [2].

For many decades, treatment of ED was carried out by specialists who did not have sufficient knowledge of the pathophysiology and mechanisms of erection. Thus, in 1668, intracavernosal injections of salt solutions were first performed, then numerous options for oral therapy with various tinctures (for example, from animal testicles) were used; in the 19th century, subcutaneous injections of ejaculate were proposed; in 1936, the first penile implantation was performed [3 ].

Currently, in the treatment of ED, the polyetiological nature of the disease is taken into account, but the first line of therapy, despite the variety of causes of ED, are phosphodiesterase type 5 inhibitors (PDE-5 inhibitors). The noninvasive nature of PDE5 inhibitor therapy has increased the availability of treatment compared to other treatment modalities, which include intracavernous injections of vasoactive drugs, vacuum devices, penile prostheses, and surgical vascular reconstructions [3].

The history of the use of PDE-5 inhibitors began in March 1998, when the drug sildenafil was approved for use by the Food and Drug Administration (FDA) in the United States of America. With the appearance on the market of this first effective tablet drug for the treatment of ED, sildenafil rightfully became the flagship and gold standard of first-line treatment for ED. Vardenafil and tadalafil, which were introduced somewhat later, are also known as selective PDE5 inhibitors. Thus, sildenafil is the most studied drug among PDE-5 inhibitors in terms of safety and effectiveness.

Sildenafil citrate provides an increase in the concentration of cyclic guasine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum of the penis, which, in turn, leads to an increase in the level of nitric oxide (NO) in these cells and, as a result, to the relaxation of these cells and increased blood flow in the penis. When the NO-cGMP chain is activated, which is observed during sexual arousal, inhibition of PDE5 leads to an increase in cGMP in the corpus cavernosum. The pharmacological effect is achieved only in the presence of sexual stimulation [4].

USE OF SILDENAFIL IN PATIENTS WITH CARDIOVASCULAR DISEASES

In the American Massachusetts Male Aging Study, the incidence of ED in men aged 40-70 years was 52%. In the German study Cologne Male Survey, when analyzing the population, the incidence of ED was 10% in men aged 40-49 years, 16% in men aged 50-59 years, 34% in men aged 60-69 years and more than 50% in men aged from 70 to 80 years [5-7]. Thus, the main group of patients with erectile dysfunction are men over 50 years old; at this age, the incidence of cardiovascular diseases, including myocardial infarction and stroke, increases. Sexual dysfunction in men with cardiovascular disease is common. Many patients stop sexual activity due to fear that physical efforts during sexual activity will be complicated by recurrent myocardial infarction. However, there are a number of studies proving the safety and effectiveness of sildenafil citrate in a group of patients with ED and cardiovascular diseases [8-9].

In a phase II/III, double-blind, open-label study conducted by the FDA, more than 3,700 patients received sildenafil for ED and nearly 2,000 received placebo. Approximately 25% of patients had hypertension and were taking antihypertensive drugs, and 17% had diabetes. In these studies, the incidence of major cardiovascular events was similar in the sildenafil and placebo groups. 28 patients who suffered myocardial infarction during the study were registered. The incidence of myocardial infarction was 1.7% in the sildenafil group and 1.4% in the placebo group. There were no differences in the incidence of cardiovascular disease between the two groups, and no deaths were related to treatment. Histomorphological studies did not find any traces of PDE-5 inhibitors in the area of necrosis and tissue of the ventricles of the heart, but traces of PDE-5 inhibitors were found in the atria [10].

In studies by M. Guazzi et al. It was found that sildenafil improves the condition of the endothelium. The authors noted flow-dependent dilatation of the brachial artery in patients with heart failure and type 2 diabetes mellitus [11].

In patients with heart failure due to ischemic or non-ischemic heart disease without pulmonary disease, a single dose of 50 mg of sildenafil caused a significant increase in cardiac index and a decrease in pulmonary vascular resistance both at rest and during exercise. In patients with coronary artery diseases, a positive effect of sildenafil on skin microcirculation has been established [12].

The vasodilator effect of sildenafil affects both arteries and veins, so the most common side effects are headache and facial flushing. Sildenafil causes a slight decrease in systolic and diastolic blood pressure, but clinically significant hypotension is rare, while co-administration of sildenafil and nitrates causes a more significant drop in blood pressure. For this reason, sildenafil is contraindicated for use in patients within 24 hours after taking short-acting nitrates. Meanwhile, about 5.5 million men require constant intake of nitrates, which leaves the question of further research on the joint use of these substances open [9].

USE OF SILDENAFIL IN PATIENTS WITH DIABETES MELLITUS

In the practice of a therapist, a pressing issue is the use of sildenafil for diabetes mellitus, since in patients suffering from type 1 and type 2 diabetes mellitus, erectile dysfunction occurs three times more often than in the general patient population. Moreover, erectile dysfunction can be considered as an early marker of diabetes mellitus. Thus, 12% of men suffering from erectile dysfunction were diagnosed with diabetes mellitus for the first time during examination. An additional 50% are expected to develop ED within 5–10 years of diagnosis [13]. The mechanism of ED in men with diabetes mellitus is predominantly caused by organic factors: vasculogenic and neurological. Goldstein et al. A study of sildenafil citrate 50 mg in patients with diabetes reported a 52% improvement in erectile function compared with placebo [14]. Similar data were obtained by MS Rendell et al. They noted an improvement in erectile function in 56% of patients taking sildenafil at a dosage of 100 mg versus 10% in the placebo group. Thus, sildenafil is effective and well tolerated in the treatment of organic ED in men with diabetes mellitus [15].

USE OF SILDENAFIL IN PSYCHOTHERAPY PRACTICE

Erectile dysfunction is a polyetiological disease and in some cases can be caused by various psychogenic factors that require specialized therapy. ED can both cause depression and be its consequence.

It has been noted that with monotherapy with antidepressants, antidepressant-induced ED occurs in 37% of cases, manifested by decreased libido, difficult ejaculation and anorgasmia. In a 12-week randomized, double-blind, placebo-controlled study in 20 urology clinics, the effect of sildenafil on erectile dysfunction in men with mild to moderate depressive disorders was assessed. Not only has sildenafil been shown to be an effective drug for the treatment of erectile dysfunction, but it has also been associated with a marked reduction in depressive symptoms and an improvement in quality of life: 60 (90.9%) of 66 men taking sildenafil reported that the treatment improved their erections and 59 (89.4%) %) noted an improvement in the ability to perform sexual intercourse, compared with 8 (11.4%) and 9 (12.9%) of 70 men receiving placebo, respectively [16-17].

A meta-analysis of 9 randomized studies was conducted involving 398 men with ED of mixed etiology who received various treatments: 141 patients used psychotherapy only, 109 only sildenafil, 68 patients used psychotherapy in combination with sildenafil, 20 people used vacuum devices and 59 people included to the control group. The best rates of successful treatment were obtained for a group of patients in which psychotherapeutic treatment was combined with sildenafil [18].

Another study assessed the effect of sildenafil on couple mental health using the Self-Esteem And Relationship (SEAR) questionnaire. According to the results of the survey, after a year of taking the drug, indicators such as general well-being, self-control, and satisfaction in relationships increased significantly. The authors recommend taking the drug to improve the overall mental health of not only the man, but also the couple as a whole [19].

SELECTED ISSUES OF THE APPLICATION OF SILDENAFIL IN VARIOUS UROLOGICAL DISEASES

Currently, the world has extensive experience in the use of sildanafil for various urological diseases complicated by ED.

Lower urinary tract dysfunction and ED

There are several clinical studies demonstrating the effectiveness of PDE5 inhibitors in the treatment of lower urinary tract dysfunction (LUTS). JP Mulhall et al. studied the effect of sildenafil on LUTS in men referred for sexual dysfunction. After the administration of sildenafil, 60% improved their IPSS questionnaire scores. The mean decrease in IPSS scores per week was 2 ± 0.6. The authors concluded that sildenafil helps improve urination in men with mild to moderate forms of LUTS and ED [20].

Many studies have been devoted to studying the role of PDE-5 inhibitors in combination with α-blockers in improving sexual function. SAKaplan et al. reported the results of their experimental work demonstrating the safety and effectiveness of combination treatment with the blocker alfuzosin and sildenafil compared with monotherapy groups in the treatment of LUTS and ED. After 12 weeks of therapy, patients in all groups showed an improvement in IPSS, Qmax and IIEF scores, but the best results were obtained in the combination therapy group. The researchers concluded that treatment with sildenafil in combination with an adrenergic blocker was safe and effective in the treatment of both LUTS and ED [21]. In another randomized, double-blind, placebo-controlled study performed by K. McVary et al. similar results were noted. In this 12-week study, 366 men over 45 years of age with IIEF-5 scores less than 25 and IPSS scores greater than 12 received sildenafil 50 and 100 mg or placebo. The results showed a reduction in mean IPSS score of 6.32 points in the sildenafil group compared to 1.93 in the placebo group. On the IIEF-5 scale, an improvement in the mean score was found by 9.17 compared to 1.86 points when taking placebo (p < 0.0001) [22].

Thus, the use of sildenafil, either alone or in combination with alpha-blockers, has demonstrated efficacy and safety in the treatment of LUTS caused by benign prostatic hyperplasia (BPH) and erectile dysfunction.

Prostate Cancer and ED

Treatment of erectile dysfunction with sildenafil in patients undergoing radiation therapy for prostate cancer (PCa) was initially shown to be effective in uncontrolled studies and later confirmed in a controlled study. 50 patients with ED after radiation therapy for localized prostate cancer took 50 mg of sildenafil. At the same time, a significant improvement in erection was noted by 66-74% of patients [23, 24].

The most significant prognostic factors for the restoration of erectile function after radical prostatectomy are bilateral preservation of the neurovascular bundles and the absence of erectile disorders before surgical treatment. According to M. Tutolo et al. The effectiveness of sildenafil for the treatment of ED in 170 men after radical nerve-sparing prostatectomy was 80% [25]. In a randomized, double-blind, placebo-controlled study, H. Padma-Nathan et al. report that early administration of a PDE5 inhibitor increases the recovery of spontaneous erections, with the effectiveness of sildenafil increasing over time, with better results observed 12–24 months after surgery [26].

Pelvic trauma and ED

Injuries to the pelvis and perineum can cause erectile dysfunction. PJ Harwood et al. noted that as a result of pelvic fracture and urethral injury, 30% and 42% of patients, respectively, had erectile dysfunction [25]. OZ Shenfield et al. reported that after urethroplasty, the administration of sildenafil at a dosage of 100 mg significantly reduced the manifestation of ED in 47% of patients. It has been noted that the drug is most effective for injuries of the genitourinary organs with preserved innervation and blood supply [27-28].

Fertility and ED

Equally important is the assessment of the effect of sildenafil on male fertility. After sildenafil entered the pharmaceutical market, many scientific works were devoted to studying the effect of the drug on the characteristics of sperm in vitro. Research by A.O. Kulikova et al., conducted at the Federal State Budgetary Institution "Research Institute of Urology" of the Ministry of Health of Russia in 2013, showed that in vitro conditions revealed a sharp increase in total sperm motility (A + B) when exposed to sildenafil at a concentration of 25 ng/ml (p < 0.001 ) and a tendency towards inhibition of general mobility (A+B) at drug concentrations above 250 ng/ml (p=0.09). This may indicate the presence of a stimulating effect on spermatogenesis and sperm maturation at a low dose of the drug. According to the data obtained, the author recommends avoiding maximum therapeutic dosages of sildenafil in patients planning pregnancy [29].

Currently, in addition to the original drug sildenafil, a generic Erexezil, produced in Hungary, has appeared on the Russian market. The results of the studies show that the effectiveness and safety of the drug Erexesil is comparable to that of the original drug [30]. Studies have noted a significant positive effect of Erexesil on erectile function. There was an improvement in the quality of life of patients taking this drug [31]. Available release forms of 50 mg and 100 mg No. 1 and No. 4 allow effective dosing of the drug, which ensures an individual approach to the treatment of each patient.

LITERATURE

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Stolk EA, Busschbach JJ. Are patients and the general public likeminded about the effect of erectile dysfunction on quality of life? // Urology. 2003. Vol. 61, N 4. P. 810-815.
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Cakir O. The frequencies and characteristics of men receiving medical intervention for erectile dysfunction: Analysis of 6.2 million patients. // 28th Annual EAU congress, 15-19 March, 2013. Milan. Italy, abst. N 126.
American Heart Association. 1998 Heart and Stroke Statistical Update. Dallas, Tx: American Heart Association; 1997.
Zusman RM. Cardiovascular data on sildenafil citrate. // Am J Cardiol. 1999. Vol. 83(1). P. 44.
Guazzi M, Tumminello G, Di Marco F, Guazzi MD. Influences of Sildenafil on lung function and hemodynamics in patients with chronic heart failure. //Clin Pharmacol Ther. 2004. Vol. 76. P. 371–8.
Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. // Circulation. 2007. Vol. 115. P. 59-66.
Shabsigh R, Perelman M, Lue TF, Broderick GA, Lockhardt D. Men's health issues: prevalence and correlates of erectile dysfunction. //Jurol. 2005. Vol. 174. P. 662–667.
Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. //N Engl J Med. 1998. Vol. 338. P.1397-1404.
Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. // JAMA. 1999. Vol. 281, N 5. P. 421-426.
Seidman SN, Roose SP, Menza MA, Shabsigh R, Rosen RC. Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. //Am J Psychiatry. 2001. Vol. 158. P. 1623–1630.
Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. //Psychopharmacol Bull. 1997.Vol. 33. P. 755-760.
Melnik T, Soares B, Nasello AG. Psychosocial interventions for erectile dysfunction. //Cochrane Database of Systematic Reviews. 2007. Vol 3.
O'Leary MP, Althof SE, Cappelleri JC, Crowley A, Sherman N, Duttagupta S. Selfesteem, confidence and relationship satisfaction of men with erectile dysfunction treated with sildenafil citrate: a multicentre, randomized, parallel group, double-blind, placebo controlled study in the United States. // J Urol. 2006. Vol. 175. P. 1058–1062.
Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. //J Sex Med. 2006. Vol. 3, N 4. P. 662-667.
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Journal "Experimental and Clinical Urology" Issue No. 1 for 2015

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Contraindications

The use of Silenafil has a fairly wide range of contraindications:

hypersensitivity to the active substance or auxiliary components of the drug;
severe disturbances in liver function;
low blood pressure (less than 90/50);
recently suffered pathologies associated with cerebral circulatory disorders;
recent myocardial infarction;
phenylkenothuria;
loss of vision in one eye;
hereditary retinal dystrophy;
simultaneous use with Amylnitrite, nitrates and other nitric oxide NO donors;
simultaneous use with the drug "Ritonavir";
children under 18 years of age.

There are other contraindications. For example, the drug is not recommended for use by men who should not be sexually active due to severe heart failure.

Hypertensive patients with blood pressure above 170/100 should take this medication with caution, as well as in the presence of:

severe arrhythmia that threatens life;
left ventricular obstruction;
conditions that predispose to prialism;
ischemic optic neuropathy;
anatomical deviations of the penis (deformation, Peyronie's disease and others).

Causes of erectile dysfunction

Traditionally, the causes of erectile dysfunction are divided into organic and psychogenic. However, psychogenic factors, as a rule, are secondary in nature, reflecting the response of the patient’s higher nervous activity to a primary violation of sexual function. Thus, in the vast majority of cases, ED is caused by organic disorders of the blood circulation and innervation of the penis, which is confirmed by numerous fundamental studies of the mechanisms of erection and clinical experience in treating patients with ED.

Among the organic causes of erectile dysfunction are hormonal disorders associated with a primary or secondary decrease in testosterone levels due, for example, to trauma, inflammation of the testicles, or increased levels of prolactin in the body, which suppresses testosterone production. ED can also be caused by systemic damage to the vascular bed as part of atherosclerosis, diabetic macroangiopathy and neuropathy, autointoxication as part of renal and liver failure, demyelinating diseases of the central nervous system (multiple sclerosis, Alzheimer's disease), and exposure to medications (antidepressants). In addition, ED can be caused by traumatic disruption of the innervation and blood circulation of the penis as a result of operations on the pelvic organs, radiation and various injuries. A separate group of causes includes ED, which occurs as a result of the loss of the veno-occlusive mechanism in the veins of the penis, which leads to rapid loss of erection.

Based on the above facts, the appearance of erectile dysfunction in socially active men should be a reason to consult a doctor. Unsubstantiated advertising of herbal medicines and dietary supplements in the media has led to patients self-medicating for a long time. They often turn to specialists already having severe vascular and neurogenic disorders, accompanied by severe fibrosis of the corpora cavernosa, which leads to an increase in the frequency of penile arthroplasty.

Side effects

In some cases (often due to an overdose), minor side effects are possible:

dyspepsia;
dizziness;
headache;
feeling of nasal congestion;
flushes of blood;
temporary vision problems;
noise in ears;
hypersensitivity reactions.

In rare cases, the following were observed:

temporary deafness;
cardiopalmus;
nosebleeds;
skin rash;
nausea;
myalgia;
chest pain;
fast fatiguability;
an erection that lasts too long.

Sildenafil-fpo, 10 pcs., 100 mg, film-coated tablets

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination. Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section "Caution" ).

During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, you should immediately seek medical help. If priapism is not treated immediately, it can lead to damage to the tissue of the penis and irreversible loss of potency.

Medicines intended to treat erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable. Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for a cardiovascular examination.

Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, hypertension (BP > 170/100 mmHg) or hypotension (BP < 90/50 mmHg) .). Taking sildenafil in such patients is contraindicated (see section "Contraindications"). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of death from cardiovascular diseases (0.3 per 100 people per year) in patients receiving Sildenafil-FPO®, according to compared with patients receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported ), which had a temporary association with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing Sildenafil-FPO®, the physician must carefully assess the risk of possible undesirable manifestations of the vasodilating effect in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the combined use of sildenafil and α-blockers can lead to symptomatic hypotension in some sensitive patients, the drug Sildenafil-FPO® should be prescribed with caution to patients taking α-blockers (see section “Interaction with other drugs”). To minimize the risk of developing postural hypotension in patients taking α-blockers, Sildenafil-FPO® should be started only after stabilization of the patient's hemodynamic parameters. You should also consider the advisability of reducing the initial dose of Sildenafil-FPO® (see section "Method of administration and dosage"). The physician should inform patients about what actions to take if symptoms of postural hypotension occur.

Visual impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and cause of vision loss or reduction, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. Results indicate an approximately 2-fold increase in the risk of NPINSID within 5 half-lives of PDE5 inhibitor use. According to the published literature, the annual incidence of NPINSID is 2.5-11.8 cases per 100,000 men aged ≥ 50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPIND have an increased risk of recurrent NPIND. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk. In patients with episodes of NPINS with loss of vision in one eye, sildenafil is contraindicated (see section "Contraindications"). A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of using Sildenafil-FPO® in patients with retinitis pigmentosa, therefore sildenafil should not be used in such patients (see section “Contraindications”).

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. If there is a sudden deterioration in hearing or hearing loss while taking sildenafil, you should consult your doctor immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of the use of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, therefore the drug Sildenafil-FPO® should be used with caution in these patients (see section "With caution"). The incidence of epistaxis in patients with PH associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary arterial hypertension (sildenafil 3.0%, placebo 2.4%) . Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not receiving a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction

The safety and effectiveness of Sildenafil-FPO® in combination with other PDE5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil (for example, Revatio®) or other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section "Contraindications" "). Effect on the ability to drive a car and operate machinery Since when taking sildenafil, dizziness, decreased blood pressure, development of chromatopsia, blurred vision, etc. are possible. side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Also, you should be careful about the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

"Sildenafil": instructions for use

The drug is taken orally and washed down with a small volume of water. The standard single dosage is 50 mg one hour before sexual intercourse. If the effect is insufficient, increase the dosage by 2 times (subject to normal tolerance and absence of contraindications). The maximum amount per day is 100 mg, frequency of use is 1 time per day.

For older people, the same dosages are established. In this case, the daily intake rate can be adjusted in the presence of certain diseases:

Renal dysfunction – 25 mg.
Liver dysfunction – 25 mg.
Simultaneous use with other drugs such as Ketoconazole, Cimetidine (except Ritonavir), Erithoromycin - up to 25 mg.

These restrictions are not “hard” ones. If the effect is insufficient, the daily dosage can be gradually increased to 50 mg, then to 100 mg.

Description of the drug SILDENAFILUM

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 40% (25-63%). After a single oral dose of 100 mg, Cmax is 18 ng/ml and is achieved when taken on an empty stomach for 30-120 minutes. When taking sildenafil in combination with fatty foods, the rate of absorption is reduced; Tmax increases by 60 minutes, and Cmax decreases by an average of 29%. The Vd of sildenafil at steady state is on average 105 liters. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of the total concentration of sildenafil. Less than 0.0002% of the dose (mean 188 ng) was detected in semen 90 minutes after sildenafil administration.

Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (the main route) and CYP2C9.

The main circulating metabolite, which is formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil itself. The concentration of the metabolite in plasma is approximately 40% of that of sildenafil. The N-desmethyl metabolite undergoes further metabolism; its terminal T1/2 is about 4 hours.

The total clearance of sildenafil from the body is 41 l/h, and T1/2 in the terminal phase is 3-5 hours. After oral administration, sildenafil is excreted in the form of metabolites mainly in feces (approximately 80% of the dose) and to a lesser extent in urine ( approximately 13% of the dose).

In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of the free active substance in plasma is approximately 40% higher than its concentration in young (18-45 years) patients.

In case of mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal failure, the pharmacokinetic parameters of sildenafil after a single oral dose (50 mg) do not change. In severe renal failure (creatinine clearance ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, resulting in an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age group .

special instructions

One-time use is allowed without consulting a doctor, except in cases associated with severe pathologies of the cardiovascular system, kidneys or liver. For long-term use, preliminary consultation with a specialist is recommended.

In extremely rare cases, cardiac instability may occur. In case of overdose, myocardial infarction, including death, cannot be ruled out. Complications can develop during, after, or even without sexual intercourse.

Sildenafil leads to dilation of blood vessels, which leads to a slight, reversible decrease in blood pressure. Therefore, on the eve of the appointment, the doctor should assess the possible risks associated with a decrease in blood pressure.

Mechanisms of occurrence and maintenance of erection

Let us briefly describe the basic mechanisms of the occurrence and maintenance of an erection. Somatic innervation of the penis is carried out from the sacral erection center, which is located at the level of S2–S4. In the latter, impulses come from the cerebral cortex as a result of audiovisual and tactile stimulation. At the endings of the efferent fibers, nitric oxide is released, which is the main mediator of relaxation of the vascular bed of the corpora cavernosa of the penis. The production of nitric oxide in the endothelium of the vessels of the cavernous bodies leads to the expansion of the latter and the occurrence of an erection. Nitric oxide is synthesized from the amino acid L-arginine after exposure to the enzyme NO synthetase. By penetrating the cell membrane and activating the system for the production of cyclic guanosine monophosphate (cGMP), nitric oxide leads to relaxation of the smooth muscle cells of the vessels of the cavernous bodies of the penis both during systole and diastole. To maintain an erection during the time required for sexual intercourse, the inclusion of mechanisms that prevent the outflow of venous blood from the penis is required. This effect is achieved by compression of the venous plexus between the tunica albuginea and the cavernous sinuses. Additional compression is carried out using voluntary contraction of the ischiocavernosus muscles. The enzyme cGMP phosphodiesterase type 5 blocks the intracellular cGMP production system, thus causing detumescence. The sympathetic innervation of the penis is also responsible for the cessation of erection; the sympathetic center is located at the Th4–L2 level, and the effect occurs through the release of norepinephrine and interaction with alpha-adrenergic receptors of cavernous smooth muscle cells. Subsequently, smooth muscle cells contract, which leads to loss of erection.

Drug treatment of erectile dysfunction

Phosphodiesterase type 5 inhibitors affect the relaxation of smooth muscle cells through competitive interaction with phosphodiesterase type 5 and promote the accumulation of cGMP inside cavernous smooth muscle cells, as well as in the cells of the smooth muscle layer of the penile arteries. Today, there are five drugs in the class of phosphodiesterase type 5 inhibitors on the market: sildenafil, vardenafil, tadalafil, udenafil and afanafil. All of them are characterized by a similar mechanism of action and approximately the same safety profile. Currently, according to the recommendations of the European and American Urological Associations, a particular drug is prescribed depending on the patient’s preferences or personal experience, as well as in accordance with the recommendations of the urologist. Accordingly, in order to instruct the patient and determine the optimal dosage regimen for the drug if the patient has concomitant diseases, the physician must know the pharmacokinetic and pharmacodynamic characteristics of the drugs.

Clinical efficacy of sildenafil

Sildenafil is the most studied drug from the entire group of phosphodiesterase type 5 inhibitors. In addition, it is a reference drug for comparative clinical studies of the effectiveness of other phosphodiesterase type 5 inhibitors.

Sildenafil began to be used in the late 1990s, so the experience of its use exceeds 15 years. The history of the discovery of sildenafil is widely known: during clinical trials of the new antianginal drug, scientists noted a side effect, which was the improvement of erectile function. Moreover, unlike other drugs for the treatment of ED on the market at that time, no cases of priapism were observed while taking it.

The emergence of sildenafil prompted a number of clinical studies in this area. The term “impotence” has been replaced by the concept of “erectile dysfunction”, which implies the potential possibility of correcting existing disorders in the sexual sphere. Clinical studies of sildenafil have led to the development of new diaries and questionnaires to assess the state of male sexual function. Analysis of demographic indicators of participants in large-scale clinical trials made it possible to identify risk factors for ED, which in turn contributed to understanding the mechanisms of its development. Evidence has begun to accumulate that most cases of ED have an underlying somatic nature, and psychological problems are often secondary to primary vascular or nerve damage. Patients with erectile dysfunction who had not previously consulted a doctor received hope for improved sexual function, and to date, millions of men around the world have returned to their sexual lives thanks to taking this drug.

The clinical effectiveness of sildenafil citrate has been studied in numerous studies. One of the largest meta-analyses combined data obtained from 11 double-blind, placebo-controlled studies, which included a total of more than 2,500 patients with erectile dysfunction [4]. In the main group, an improvement in erection was noted in 76% of patients versus 22% in the placebo group, which led to a significant difference in the frequency of successful attempts at sexual intercourse - 66 and 26%, respectively. The effectiveness of various dosages of the drug was 65% for 25 mg, 74% for 50 mg and 82% for 100 mg. The high effectiveness of sildenafil was noted in different age groups. In the category of patients under 65 years of age, the effectiveness of the drug was 77.6% versus 69.2% in the older age group. According to research, the drug is effective compared to placebo in patients with erectile dysfunction, regardless of the cause of its development and severity.

Despite the high effectiveness of therapy with phosphodiesterase type 5 inhibitors, there remains a certain cohort of patients in whom taking this drug does not lead to an improvement in erection. Possible causes include improper medication administration [5]. Patients, especially at the beginning of treatment, should be advised to take sildenafil on an empty stomach at least 30 minutes before the planned start of sexual intercourse. Patients should be informed that the effect of the drug develops only against the background of adequate sexual arousal and largely depends on it. In many cases, treatment should begin with a maximum therapeutic dosage of 100 mg, which will allow for maximum results at the beginning of treatment and instill confidence in the success of therapy. In addition, studies have shown that in some patients the maximum effect of sildenafil is achieved by the sixth to eighth dose, and therefore in many patients the final assessment of the effectiveness of the drug should be made after several attempts to use it.

Sildenafil in the treatment of erectile dysfunction after prostatectomy

Effective selection of therapy for ED after prostatectomy is currently one of the urgent problems of urology, which is due to the increase in the number of operations, the development of nerve-saving surgical techniques, and the introduction of robotics. Numerous studies have examined risk factors for the onset of ED after surgery: type of surgery (non-nerve-sparing, mono- or bilateral nerve-sparing techniques), patient age, preservation of erection before surgery, socio-economic conditions (level of education, patient income), tumor stage, prostate size , urologist experience.

R. Raina et al. showed that sildenafil therapy is effective in 71.7% of patients after bilateral nerve-sparing surgery, in 50% after unilateral nerve-sparing prostatectomy and in 15% of patients after non-nerve-sparing surgery. It has been shown that one of the features of ED after radical prostatectomy is the possibility of progressive improvement of erection several years after surgery, therefore, long-term follow-up is necessary to make a final judgment about the effectiveness of therapy [6].

EK Hong et al. observed 316 patients with ED after radical prostatectomy, which in 95% of cases was bilateral nerve-sparing. The effectiveness of sildenafil was 26% during the first 6 months, 36% from 6 to 12 months, 50% from 12 to 18 months and 60% from 18 to 24 months after surgery [7].

Currently, most authors believe that to prevent the development of ED after radical prostatectomy, long-term use of phosphodiesterase type 5 inhibitors, and in particular sildenafil, in low therapeutic doses is necessary. This therapy is justified by data on the improvement of blood flow in the corpora cavernosa against the background of long-term continuous use of drugs, which serves as prevention of the development of a local scar-sclerotic process. H. Padma-Nathan et al. studied the effectiveness of sildenafil in the prevention of ED after radical prostatectomy [8]. As a result of the study, patients who underwent bilateral nerve-sparing surgery and did not suffer from ED before surgery, starting from the second month of the postoperative period, received sildenafil in doses of 100 and 50 mg or placebo at bedtime for 36 weeks. Eight weeks after stopping treatment, 27% of men receiving sildenafil reported the ability to lead a normal sexual life, compared with only 4% of those receiving placebo [8].

Sildenafil therapy can be an effective method of preventing ED in patients after radical prostatectomy as a result of improving the blood supply to the cavernous tissue, preventing the development of fibrotic changes in it. Long-term use of the drug in small doses for the rehabilitation of patients after transurethral and oncoproctological operations is based on the same principles [8].

Sildenafil-sz tablet p/o film 100mg 14 pcs

Pharmacological group:

A treatment for erectile dysfunction is a PDE5 inhibitor.
Pharmacodynamics:
Sildenafil is a powerful selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Mechanism of action. The physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and increased blood flow. Sildenafil does not have a direct relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP. Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds that of other known phosphodiesterase isoenzymes: PDE6 – 10 times; PDE1 – more than 80 times; PDE2, PDE4, PDE7-PDE11 – more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data.

Cardiac research.

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg. Art., and diastolic pressure – 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure (BP) was observed in patients taking nitrates (see sections “Contraindications” and “Interaction with other drugs”). In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (CAD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic blood pressure decreased by 7 % and 6%, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries. In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds; 0.9 - 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo. A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.

Studies of visual impairments.

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter. In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Humphrey perimeter, and photostress).

Efficiency.

The efficacy and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview. The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients reporting that therapy improved their erections was: 62% (25 mg sildenafil dose), 74% (50 mg sildenafil dose), and 82% (100 mg sildenafil dose) compared with 25%. in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improving erections, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, among patients who reported improved erections with sildenafil treatment, 59% of patients with diabetes, 43% of patients who had undergone radical prostatectomy and 83% of patients with spinal cord injury (versus 16%, 15% and 12% in the placebo group, respectively) ).

Pharmacokinetics:

The pharmacokinetics of sildenafil in the recommended dose range is linear.

Suction. After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil 100 mg, the average maximum concentration of free sildenafil in blood plasma (Cmax) in men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).

Distribution. The volume of distribution of sildenafil at steady state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after dosing.

Metabolism. Sildenafil is metabolized mainly in the liver under the influence of the cytochrome CYP3A4 isoenzyme (major pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; its half-life (T1/2) is about 4 hours

Excretion. The total clearance of sildenafil is 41 l/hour, and the final T1/2 is 3-5 hours. After oral administration, as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

Pharmacokinetics in special groups of patients.

Elderly patients. In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18-45 years of age). Age does not have a clinically significant effect on the incidence of side effects

Renal dysfunction. With mild (creatinine clearance (CL) 50-80 ml/min) and moderate (CL 30-49 ml/min) degrees of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance less than 30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

Liver dysfunction. In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.

Individual selection of the dose of sildenafil in the treatment of erectile dysfunction

Erectile dysfunction (ED) is the inability to achieve and maintain an erection sufficient for sexual intercourse. This condition is not life-threatening, but significantly affects the quality of life of the patient and those around him and affects the physical and mental components of health [2]. Among men of all ages, the prevalence of ED is 10%, and it is estimated that by 2025 the number of people suffering from ED will increase to 400 million. The greatest increase is expected in developed countries [3].

Risk factors for the development of ED may be vascular (≈20%), endocrine (≈10%), neurological diseases (≈20%), alcohol abuse (≈20%), side effects of medications (≈10%), psychological causes (≈ 20%), cardiovascular and systemic diseases (chronic renal failure, diabetes mellitus) and their combinations. ED of organic origin in 50–80% of men is caused by insufficiency of arterial blood supply to the penis of various origins [4–6]. The likelihood that a patient presenting with ED for the first time has coronary artery disease is estimated at 40%, and many such patients are treated with nitrates [7–9]. A multicenter, randomized, open-label study compared obese men with moderate ED who exercised for 2 years and lost weight with a control group in which patients were given the opportunity to change their diet or exercise [10]. Significant improvement in erectile function in the lifestyle group was accompanied by optimization of body mass index.

The development of diagnostic and treatment methods, fundamental research in physiology, pharmacology and other disciplines have made it possible to come closer to understanding the mechanism of erection and its disorders. At the moment of adequate sexual stimulation, relaxation of the smooth muscles of the cavernous bodies occurs. At the same time, nitric oxide is released from the presynaptic endings and the blood supply to the cavernous bodies increases. Due to their enlargement, the veins are pressed against the tunica albuginea, which leads to the cessation of venous outflow and the achievement of an erection sufficient for penetration [11–13].

It is currently believed that nitric oxide, released by non-cholinergic and non-adrenergic nerve endings, the synthesis of which occurs as a result of the action of neuronal NO synthase, plays a key role in “triggering” penile erection [14]. The physiological antagonist of NO is the vasoconstrictor, which produces anti-inflammatory, mitogenic and profibrotic effects, endothelin-1 [13]. Apparently, the interaction of these factors is a universal, general biological process [15].

Modern ideas about the physiology of erection have become the basis for various methods of treating ED [16–18]. Previously used reconstructive vascular surgical treatment methods did not provide effective results [19, 20].

In order to objectify the diverse symptoms of ED, questioning patients using questionnaires has become widespread. This method allows you to assess all components of sexual function and determine the effectiveness of the treatment methods used [21, 22].

It has been suggested that the basis of arteriogenic ED in some patients is not organic, but functional, potentially reversible damage to the arteries - endothelial dysfunction, which is currently considered as a functional stage in the development of atherosclerosis [11]. Currently, the term “endothelial dysfunction” is usually used to refer to a decrease in endothelium-dependent relaxation of smooth muscle cells [23]. A method for assessing post-occlusion changes in the diameter of cavernous arteries is proposed. The pattern revealed during the analysis of the results, which consists in the presence of signs of endothelial dysfunction in all patients with values less than 50%, indicating arteriogenic ED, is confirmation of the presence of systemic vascular diseases, which emphasizes the importance of more active identification of ED by doctors of various specialties [24, 25].

The intracavernosal injection test with vasoactive drugs does not provide complete information about the condition of the vessels. A positive result is considered to be a rigid erection that occurs 10 minutes after intracavernosal injection and lasts for 30 minutes [26]. Such a response to intracavernosal administration of a vasoactive drug indicates a functional, but not necessarily physiological, erection, since the latter can occur against the background of venous insufficiency [27]. A positive test result indicates that the intracavernosal injection method is effective for the patient. This test is not sufficient to establish a diagnosis, and a duplex ultrasound of the penile arteries is necessary.

If the maximum blood flow velocity is more than 30 cm/s, and the resistance index is above 0.8, then such indicators are considered normal [28]. If the results of the duplex study are normal, further examination of the vascular system is not required.

The primary goal of treatment for ED is to determine the etiology of the disease and, if possible, treat it, rather than treat the symptoms. This may include recommendations regarding the patient’s lifestyle and the possibility of changing them. Significant progress in understanding the peripheral physiology of penile erection has led to great advances in the pharmacological treatment of ED through the use of phosphodiesterase type 5 (PDE5) inhibitor drugs. The enzyme PDE-5 hydrolyzes cyclic guanosine monophosphate in the cavernous tissue of the penis. Inhibition of PDE5 stimulates blood flow in the penis, resulting in smooth muscle relaxation, dilation of blood vessels, and erection [29].

In 1998, the “ideal” drug for the treatment of ED was described [30]. Such a drug must be effective, safe, quickly manifest its effect and have a long-lasting effect. The effect of the drug should not be affected by food, alcohol and other drugs, it should be suitable for periodic use on demand and provide spontaneous sexual activity [31].

Sildenafil citrate is the first drug that was used to treat ED. The effect of sildenafil appears 30–60 minutes after administration. Eating a heavy, fatty meal before taking the drug reduces its effectiveness by slowing down absorption. The effect of the drug can last up to 12 hours [32]. Adverse events (headache (12.8%), flushing (10.4%), dyspepsia (4.6%), nasal congestion (1.1%), dizziness (1.2%), blurred vision (1 .9%)), as a rule, are insignificant and self-limiting. The rate of drug discontinuation due to complications is comparable to that of placebo [33]. After 24 weeks, according to the study, which revealed the effectiveness of the dose used, erectile dysfunction was observed in 56, 77 and 84% of men taking 25, 50 and 100 mg of sildenafil, respectively, compared with 25% in the placebo group [16 ].

A common, effective, affordable and convenient form of sildenafil is the drug Tornetis®. Its use statistically significantly improves the International Index of Erectile Function (IIEF) scores, the profile of sexual contacts and satisfaction with treatment.

The uniqueness of Tornetis® is not limited to its ability to provide a pronounced functional effect in the form of restoration of erection. The anti-stress properties of the drug are of a certain importance - it seems to complement the mechanism of natural limitation of the adrenergic response in extreme situations, which is the essence of the second (protective) action [34]. Rehabilitation of sexual function is achieved by a unique mechanism for individual selection of the dose of the drug.

The effectiveness of sildenafil was found in almost every group with ED. Among patients with diabetes, 66% reported improved erection, 63% reported successful attempts at sexual intercourse (28.6 and 33%, respectively, in the placebo group) [35].

Patients choose the dose of sildenafil found in Tornetis® depending on their dynamic stereotype, since the needs of men and their partners have become much more than just achieving an erection [31]. The choice of dosage and frequency of taking the drug depend on the frequency of sexual intercourse and the patient’s personal perception of the drug. Patients need to plan for the duration of the effect. Objective examination data allows us to have good grounds for selecting the optimal dose of the drug.

A necessary condition for choosing the dosage of the drug Tornetis® is the possibility of individual selection of the dose. Despite the effectiveness of PDE5 inhibitors, most patients want to reduce their use of erection-improving medications. The prescriber should also be able to titrate the dose based on its effectiveness. Sildenafil is the drug with the most experience in clinical practice. The effectiveness of sildenafil has been proven in various categories of patients. Along with these properties, patients taking Tornetis® have a unique opportunity to independently select the dosage of the drug. With the touch of a finger, a 100 mg tablet can be divided into 4 pieces of exactly 25 mg. This allows you to accurately select the dose and avoid unjustifiably taking an increased dose.

Doppler examination of the cavernous arteries is based on anatomical data and modern ideas about the physiology of erection [36, 37]. At rest, the smooth muscles of the corpora cavernosa of the penis are in a state of full contraction, peripheral resistance is high, and as a result there is moderate arterial blood flow. At the beginning of an erection, the smooth muscles of the cavernous bodies relax due to the neurotransmitter response, the resistance of the cavernous bodies decreases, and the supplying arteries dilate. This leads to increased arterial blood flow and an increase in the volume of the penis (swelling phase). Since the dense tunica albuginea has little extensibility, due to an increase in blood volume, the venules between the filled sinusoids and the tunica are compressed. Venous outflow stops, the penis becomes hard.

In the urology clinic of the First Moscow State Medical University named after. THEM. Sechenov examined 398 patients with complaints of ED. The age of the subjects was 43 (23–61) years1. All patients answered questions on the IIEF-5 scale. Of all those who applied, 25 (6.3%) had no sexual activity for at least 4 weeks. before applying. 56 (14.1%) had significant ED, 123 (30.9%) had moderate ED, 152 (38.2%) had mild ED, and 42 (10.6%) had no abnormalities (Table 1 ).

The survey data confirm the well-known fact that the main factor influencing the decline in erectile function is age (p = 0.006)2. Already on the basis of a questionnaire, it is possible to objectify patient complaints, the degree of ED and choose a drug, its dosage and duration of use. Logic dictates that when ED symptoms are most severe, a larger amount of the drug is indicated.

During the history collection process, no risk factors for ED were identified in 281 (70.6%) patients. In 62 (15.6%) patients, vasculogenic risk factors (atherosclerosis) were identified, in 30 (7.5%) - neurogenic factors (diabetic, alcoholic polyneuropathy), in 25 (6.3%) - others (taking calcium channel blockers , angiotensin-converting enzyme inhibitors, drug use). The distribution of patients with or without sexual activity depending on the presence and type of risk factors was not significant (p=0.062)3. The severity of ED was statistically associated with vasculogenic and neurogenic risk factors (p=0.001)4. Thus, anamnestic data can also serve as a basis for choosing a drug and its dosage.

The method of differential diagnosis of forms of ED by pharmacodopplerography using oral administration of a PDE-5 inhibitor and assessing changes in Doppler ultrasound parameters does not allow determining the degree of venous “leakage” as the cause of ED [38]. Injection of a vasodilator into the corpus cavernosum is a useful, inexpensive, and minimally invasive diagnostic method in patients with suspected vasculogenic ED [39].

For the purpose of pharmacodopplerography of the cavernous arteries, we used alprostadil, a naturally occurring form of prostaglandin E1, which has a wide spectrum of pharmacological action. Among its most significant effects are vasodilation and suppression of platelet aggregation. When administered intracavernosally, alprostadil inhibits α1-adrenergic receptors in tissues, relaxes the muscles of the cavernous bodies, increases blood flow and improves microcirculation. Alprostadil causes erection by relaxing the trabecular smooth muscle of the corpus cavernosum and dilating the cavernous arteries, which leads to expansion of the lacunar spaces and occlusion of blood flow by pressing the venules against the tunica albuginea (penile vein occlusion).

To study blood flow, a linear sensor with a frequency of 7 MHz is used. It is used to assess the condition of the cavernous arteries before and after intracavernous administration of prostaglandin E1 using a 27–30 G needle. The dose of alprostadil was 5 mcg.

In Russia, the first experience of using prostaglandin E1 in the diagnosis and treatment of ED was reported in 1995 [40]. Then there was a proposal to use and even produce prostaglandin E1 in a dosage of 5 mcg for diagnostic purposes. Most sources describe prostaglandin dosages of 10 to 20 mcg [36, 41–44]. However, there are indications that the amount of the drug must be differentiated: in patients under 50 years of age, 5 mcg of the drug should be administered, and in patients over 50 years of age – 10 mcg [39]. The test result was assessed 15 minutes after intracavernous injection. The degree of erection was determined in accordance with the degree of swelling and rigidity of the penis (Table 1) [4, 43]. The clinical result of the test with alprostadil is presented in Table 2.

15 minutes after administration of 5 μg of alprostadil, various combinations of swelling and rigidity of the penis were obtained, while there was no sexual stimulation during the study.

We noted that the clinical result of intracavernosal administration of alprostadil significantly depended on age (p = 0.008)5. Younger patients had higher degrees of swelling and stiffness than older patients. Moreover, the presence or absence of identified risk factors did not have a statistically significant effect on the clinical result of the intracavernous test (p = 0.29)6. Also, the test result did not depend on the type of ED risk factors (p=0.064)7.

A statistically significant distribution of patients was revealed depending on the degree of swelling and rigidity of the penis after intracavernosal administration of alprostadil and the results of a questionnaire on the IIEF-5 scale (p = 0.011)8. In patients with preserved sexual activity, the clinical result of intracavernosal administration of the drug was significantly better (p = 0.002)9. Thus, a clinical assessment of the intracavernous test in combination with anamnesis data and the results of the questionnaire will make it possible to clarify the cause and type of ED with a sufficient degree of probability.

Along with assessing the effectiveness of alprostadil administration, the spectral characteristics of blood flow in the cavernous arteries were analyzed. The maximum systolic velocity was measured in the area of the proximal third of the penis, since at this level the velocities have the greatest values. If blood flow velocity is measured in the distal region, the results are underestimated.

Spectral Dopplerography of the cavernous arteries began 5 minutes after injection and then repeated every 5 minutes until the 25th minute. After administration of drugs containing prostaglandins, the blood flow velocity should be at least 35–40 cm/s [36, 45].

Pathological venous outflow was suspected if there was adequate arterial inflow, an erection developed, but its duration was short, and constant antegrade diastolic blood flow was determined throughout the study. Constant diastolic blood flow is the preservation of the speed of diastolic blood flow throughout all stages of erection. The speed value is determined after correction for the angle. Another sign of venous outflow is the resistance index. This is a reliable method for diagnosing cavernous venous drainage. A resistance index of less than 0.75 is accompanied by venous outflow in 90% of patients. A resistance index of more than 0.9 is observed in 90% of healthy subjects.

When assessing the results, we were guided by the recommendations of the European Society of Urology (peak systolic blood flow - above 30 cm/s, resistance index - above 0.8) [46].

First of all, we clarified the symmetry of blood flow in the right and left cavernous arteries after the administration of prostaglandin E1. Blood flow velocity (p=0.662) and resistance index (p=0.297) did not have significant differences. Therefore, for further evaluation, indicators of one artery are presented10. The results of pharmacodopplerography of the cavernous arteries are presented in Table 3, from which it can be seen that the clinical result of this study of the cavernous arteries depends on the maximum blood flow velocity and blocking of venous outflow after intracavernous administration of 5 μg of prostaglandin E1.

The maximum blood flow velocity in the cavernous artery during control measurements was higher in young patients compared to older groups (p = 0.001). Also, the resistance index was higher in young patients (p=0.001)11. Thus, age affects not only the clinical signs and severity of ED, but also the objective parameters of blood flow in the cavernous arteries.

The presence or absence of intimate activity for at least 4 weeks. before the study did not have a significant effect on the maximum blood flow velocity (p = 0.291) and the resistance index (p = 0.187)12.

The maximum blood flow velocity was significantly lower (p=0.002) in patients with identified risk factors for ED (vasculogenic, neurogenic, etc.). Moreover, the resistance index did not depend on risk factors (p=0.255)13. The maximum blood flow velocity in the cavernous arteries did not depend on the degree of erectile dysfunction, as determined by questionnaire data on the IIEF-5 scale (p = 0.901)14. There was also no correlation between the resistance index (p=0.226)15.

The clinical result of intracavernosal administration of alprostadil (degree of filling and penile rigidity) is most pronounced in young patients. The presence and type of risk factors did not have a significant effect on the clinical result of the test. In patients with preserved sexual activity, the clinical result of intracavernosal administration of the drug was significantly better. This aspect of the study allows us to imagine the influence of psychological or organic causes of ED.

The maximum blood flow velocity and resistance index in the cavernous artery after the administration of alprostadil were higher in young patients. The presence or absence of intimate activity had no significant effect on the spectral characteristics of blood flow. The influence of established risk factors on the maximum velocity of blood flow in the cavernous arteries was noted.

Thus, the use of 5 mcg of alprostadil is an effective and safe method for examining patients with ED of various origins and severity. This made it possible to clarify the hemodynamic causes of complaints of ED (Table 4).

The absence of hemodynamic changes was detected in 244 (61.3%) patients, insufficient arterial inflow - in 67 (16.8%), venous leakage with sufficient arterial inflow - in 51 (12.8%), a combination of insufficient inflow and venous leakage - in 36(9.0%) patients.

Data from pharmacodopplerography of the penis also make it possible to select the dosage of sildenafil depending on the presence and combination of hemodynamic causes of ED. Tornetis® has the most acceptable form of application. The unique split technology of the Tornetis® tablet allows you to select the dose for the patient. With one click, the tablet is precisely divided into equal parts of 25 mg. For patients of older age groups with the presence of risk factors and a combination of hemodynamic reasons, the maximum dosage of Tornetis® is indicated (100 mg). For young patients with no hemodynamic changes according to pharmacodoppler ultrasound, the minimum dose of Tornetis® (25 mg) is indicated. This allows you to get maximum effectiveness and reduce the likelihood of side effects.

Thus, Tornetis® is a unique dosing system, the ability to individually select the dose according to the patient’s needs, and adequate effectiveness after each dose.

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[1] The median is indicated, as well as the 5th and 95th percentiles

[2–4] Chi-square test applied

[5–9] Chi-square test applied

[10] Wilcoxon test applied

[11–15] Kruskall–Wallis test applied