G.04.B.E Drugs for the treatment of erectile dysfunction

G.04.B.E.03 Sildenafil

Sildenafil is a drug for the treatment of erectile dysfunction, belonging to the group of phosphodiesterase type 5 inhibitors (PDE-5). Provides a stable and full erection, sufficient for sexual intercourse. Sildenafil is the active ingredient of the legendary Viagra, but in Russia it is also produced under its "maiden name" (read: under the international non-proprietary name). Sildenafil was synthesized in 1998 and became the first truly effective and safe tablet drug for the treatment of such a common disease today as erectile dysfunction. To understand the mechanism of action of sildenafil, it is necessary to delve a little into the biochemical "wilds". First of all, it should be noted what an important role in the functioning of the cardiovascular system is played by the endothelial relaxing factor, also known as nitric oxide (NO). Formed in the vascular endothelium, NO penetrates into the smooth muscle tissue, where it "wakes up" ... no, not Herzen, but the enzyme guanylate cyclase. As a result, the cellular concentration of cyclic guanosine monophosphate (abbreviated as cGMP) increases sharply, which, in turn, prevents the penetration of calcium ions into the cells, which entails a decrease in vascular tone. But there is also a negative character here - the enzyme phosphodiesterase (PDE). It destroys cGMP, which limits the vasodilating effect of NO. To date, it has been established that PDE-5 is the most active in this regard. Thus, inhibition of its activity enhances the effects of NO. Now you need to figure out what underlies the development of an erection. The condition for its occurrence is the relaxation of the smooth muscle "corset" of the arteries that carry blood to the cavernous bodies of the penis. This relaxation "organizes" NO secreted by endothelial cells. Sildenafil potentiates the effects of the latter by removing natural barriers to blood flow to the glans penis. The clinical efficacy of sildenafil has been demonstrated in a number of large randomized trials.

In one of them, after 12 weeks, a clear improvement in erection was noted in 76% of patients taking sildenafil, versus 22% who were content with placebo. The high efficacy of the drug was observed in representatives of different age groups: even in people over 65 years old, the drug worked in 69% of cases. One of the risk factors for erectile dysfunction is arterial hypertension. Sildenafil has a weak antihypertensive effect, however, its use by hypertensive patients who are "sitting" on antihypertensive drugs does not potentiate the effect of the latter, so such individuals can fight erectile dysfunction on a common basis. Another key risk factor for erectile dysfunction is smoking, which has not been shown in clinical trials to affect the effectiveness of sildenafil. The drug has another truly miraculous property: in patients suffering from psychogenic erectile dysfunction, it not only improves erection, but also helps to eliminate depression. A separate conversation is about persons who have developed erectile dysfunction against the background of diabetes mellitus. In this category of patients, it is most difficult to obtain a therapeutic response to pharmacotherapy. The effectiveness of sildenafil in such cases depends on the severity of diabetes and the presence of complications. However, even in such difficult conditions, the drug showed its best side: for example, in one of the clinical studies, an improvement in erection was noted in 69% of patients taking sildenafil (in fairness, it should be noted that these were patients without complications). Thus, sildenafil is clearly a "working" drug: its effectiveness does not decrease over time, which makes long-term pharmacotherapy possible. Side effects of the drug, as a rule, are mild and appear only at the beginning of treatment.

Pharmacology

Sildenafil is a potent selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Mechanism of action

The implementation of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This, in turn, leads to an increase in the level of cGMP, subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) through the inhibition of PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds activity against 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 PDEZ, which is of great importance, since PDEZ 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 mm Hg. Art., and diastolic pressure - 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure was noted in patients taking nitrates.

In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), systolic and diastolic pressure at rest decreased by 7% and 6%, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenotic coronary arteries, and also led to an increase (by approximately 13%) of 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 who were taking antianginal drugs (except nitrates) performed physical exercise until the severity of angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds; 0.9 - 38.9 seconds) in patients taking sildenafil at a single dose of 100 mg compared with patients receiving placebo.

In a randomized, double-blind, placebo-controlled study, the effect of changing the dose of sildenafil (up to 100 mg) was studied in men (n = 568) with erectile dysfunction and arterial hypertension taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The frequency of adverse effects was comparable to that in other groups of patients, as well as in individuals taking more than three antihypertensive drugs.

Research on visual impairment

In some patients, 1 hour after taking sildenafil at a dose of 100 mg using the Farnsworth-Munsel 100 test, a slight and transient impairment in the ability to distinguish shades of color (blue / green) was detected. 2 hours after taking the drug, these changes were absent. It is believed that the violation of color vision is caused by inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electro-retinogram, intraocular pressure or pupil diameter.

In a placebo-controlled crossover study of patients with proven early age-related macular degeneration (n = 9), sildenafil at a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by special visual tests (visual acuity, Amsler grating, color perception, color passage simulation, Humphrey perimeter and photostress).

Efficiency

The efficacy and safety of sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3000 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, an international index of erectile function (a validated questionnaire on the state of sexual function) and a partner survey.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies conducted and has been confirmed in long-term studies lasting 1 year. In fixed-dose studies, the ratio of patients reporting that the therapy improved their erections was: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose) and 82% (sildenafil 100 mg dose) compared to 25% in the placebo group. An analysis of the international index of erectile function showed that, in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, made it possible to achieve satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, 59% of patients with diabetes, 43% of patients who underwent radical irostatectomy and 83% of patients with spinal cord injuries (vs. ).

Pharmacokinetics

Suction

Sildenafil is rapidly absorbed after oral administration. 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 at a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng / ml (38 nM). C max 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 absorption rate decreases: C max decreases by an average of 29%, and TC max increases by 60 minutes, but the degree of absorption does not change significantly (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%) .

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 liters. The relationship of sildenafil and its main circulating N-demethyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the dose of sildenafil (mean 188 ng) was found in semen 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized mainly in the liver by the cytochrome CYP3A4 isoenzyme (major pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite resulting from the N-demethylation of sildenafil undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity for PDE5 in vitro is about 50% of that 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; T 1/2 is about 4 hours.

breeding

The total clearance of sildenafil is 41 l / h, and the final T 1/2 is 3-5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted as 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 people (18-45 years). Age does not have a clinically significant effect on the incidence of side effects.

Kidney dysfunction

With mild (creatinine clearance (CC) 50-80 ml / min) and moderate (CC 30-49 ml / min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (CK< 30 мл/мин) клиренс силденафила снижается, что приводит к примерно двукратному увеличению значения AUC (100 %) и C max (88 %) по сравнению с таковыми показателями при нормальной функции почек у пациентов той же возрастной группы.

Liver dysfunction

In patients with cirrhosis of the liver (stages A and B according to the Child-Pyo 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 hepatic impairment (Child-Pyo grade C) has not been studied.

Release form

Blue film-coated tablets, round, biconvex; at the break - white or almost white.

Excipients: microcrystalline cellulose 50 mg, lactose monohydrate 61.5 mg, croscarmellose sodium 7.5 mg, povidone 4.5 mg, magnesium stearate 1.5 mg.

The composition of the film shell: Opadry II (polyvinyl alcohol, partially hydrolyzed 2 mg, titanium dioxide 1.145 mg, macrogol 1.01 mg, talc 0.74 mg, aluminum varnish based on brilliant blue 0.096 mg, iron oxide (II) yellow 0.0085 mg, iron oxide (II ) black 0.0005 mg).

1 PC. - cellular contour packings (1) - packs of cardboard.
2 pcs. - cellular contour packings (1) - packs of cardboard.
4 things. - cellular contour packings (1) - packs of cardboard.
10 pieces. - cellular contour packings (1) - packs of cardboard.
20 pcs. - polymer cans (1) - packs of cardboard.
20 pcs. - polymer bottles (1) - cardboard packs.

Dosage

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once a day.

Kidney dysfunction

< 30 мл/мин) - дозу силденафила следует снизить до 25 мг.

Liver dysfunction

Joint use with other drugs

When combined with ritonavir, the maximum single dose of Sildenafil should not exceed 25 mg, and the frequency of use should not exceed 1 time in 48 hours.

When combined with inhibitors of the cytochrome CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Sildenafil should be 25 mg. To minimize the risk of postural hypotension in patients taking α-adrepoblockers, Sildenafil should only be started after hemodynamic stabilization has been achieved in these patients. Consideration should also be given to reducing the initial dose of sildenafil.

Elderly patients

Dose adjustment of Sildenafil is not required.

Overdose

With a single dose of the drug Sildenafil at a dose of up to 800 mg, adverse events were comparable to those when taking the drug at lower doses, but were more common.

Treatment is symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, since the latter is actively bound to plasma proteins and is not excreted by the kidneys.

Interaction

Effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (the main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with the simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome CYP3A4 isoenzyme, when co-administered with sildenafil (50 mg), causes an increase in plasma concentration of sildenafil by 56%. A single dose of 100 mg of sildenafil together with erythromycin (500 mg / day 2 times a day for 5 days), a specific inhibitor of the cytochrome isoenzyme CYP3A4, against the background of achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When co-administered sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 times a day), an inhibitor of HIV protease and cytochrome isoenzyme CYP3A4, against the background of achieving a constant concentration of saquinavir in the blood, Cmax of sildenafil increased by 140%, and AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, can also cause stronger changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg 2 times a day), an inhibitor of HIV protease and a strong inhibitor of cytochrome P450, against the background of achieving a constant concentration of ritonavir in the blood, leads to an increase in Cmax of sildenafil by 300% (in 4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in plasma is about 200 ng / ml (after a single application of one sildenafil - 5 ng / ml), which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P 450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Co-administration of sildenafil with ritonavir is not recommended. If sildenafil is taken at the recommended doses by patients receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, then Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of an antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), the cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil.

Azithromycin (500 mg/day for 3 days) has no effect on AUC, C max T max, excretion rate constant and T1 / 2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other medicinal products

Sildenafil is a weak inhibitor of cytochrome P 450 -1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 isoenzymes (IC 50 >150 µmol). When taking sildenafil at recommended doses, its C max is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and with their appointment for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donators is contraindicated.

While taking the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic / diastolic blood pressure in the supine position was 7 / 7 mmHg Art., 9/5 mm Hg. and 8/4 mm Hg, respectively, and in the standing position - 6/6 mm Hg, 11/4 mm Hg. and 4/5 mm Hg, respectively. Rare cases have been reported in these patients of symptomatic postural hypotension, manifested in the form of dizziness (without syncope). In selected sensitive patients receiving α-blockers, the simultaneous use of sildenafil can lead to symptomatic hypotension.

Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme, have not been identified.

Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome isoenzyme CYP3A4, at a constant level in the blood. Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg). Sildenafil (50 mg) does not increase the hypotensive effect of alcohol in healthy volunteers, with a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with arterial hypertension, there were no signs of the interaction of sildenafil (100 mg) with amlodipine. The average additional decrease in blood pressure in the supine position is 8 mm Hg. (systolic) and 7 mm Hg. (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Side effects

Usually, the side effects of the drug Sildenafil are mild or moderate and are transient.

Fixed-dose studies have shown that the frequency

When using the drug Sildenafil in doses exceeding the recommended, adverse events were similar to those noted above, but usually occurred more often.

General condition disorders: swelling of the face, photosensitivity reactions, shock, asthenia, pain, chills, abdominal pain, chest pain.

Allergic reactions: hypersensitivity reactions (including skin rash), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Disorders from the central and peripheral nervous system: drowsiness, insomnia, hypesthesia, paresthesia, ataxia, neuralgia, neuropathy, tremor, depression, unusual dreams, decreased reflexes, stroke, transient ischemic attack, convulsions, incl. recurrent.

Cardiovascular disorders: tachycardia, increased or decreased blood pressure, myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, AV block, cerebral thrombosis, heart failure, ECG abnormalities, cardiomyopathy, sudden death, syncope.

Respiratory disorders: epistaxis, asthma, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum production, increased cough.

Gastrointestinal disorders: vomiting, nausea, dryness of the oral mucosa, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, rectal bleeding, gingivitis.

On the part of the organ of vision: eye pain, eye redness / scleral injections, conjunctival damage, lacrimation disorder, anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects, mydriasis, cataracts, eye pain.

Hearing disorders: vertigo, tinnitus, ear pain, deafness.

Blood and lymphatic system disorders: anemia, leukopenia.

Metabolic and nutritional disorders: thirst, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal disorders: arthritis, arthrosis, myalgia, tendon rupture, tendovaginitis, bone pain, myasthenia gravis, synovitis.

Skin and subcutaneous tissue disorders: urticaria, herpes simplex, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Genitourinary system disorders: cystitis, nocturia, frequent urination, gynecomastia, urinary incontinence, ejaculation disorder, genital edema, anorgasmia.

Reproductive system disorders: prolonged erection and / or priapism.

Indications

• treatment of erectile dysfunction characterized by an inability to achieve or maintain an erection of the penis sufficient for satisfactory intercourse.

Sildenafil is only effective with sexual stimulation.

Contraindications

• hypersensitivity to sildenafil or to any other component of the drug;
• use in patients receiving continuously or intermittently nitric oxide donators, organic nitrates or nitrites in any form, since sildenafil enhances the hypotensive effect of nitrates (see the section "Interaction with other drugs") Safety and efficacy of the drug Sildenafil when used together with other drugs treatment of erectile dysfunction has not been studied, so the use of such combinations is not recommended (see section "Special Instructions");
• according to the registered indication, the drug Sildenafil is not intended for use in children under 18 years of age;
• according to the registered indication, the drug Sildenafil is not intended for use in women;
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• concomitant use of sildenafil with ritonavir is not recommended.

With caution: anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease).

Diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

Diseases accompanied by bleeding.

Exacerbation of peptic ulcer of the stomach and duodenum.

Hereditary retinitis pigmentosa.

Heart failure, unstable angina, past 6 months of myocardial infarction, stroke, or life-threatening arrhythmias, hypertension (BP > 170/100 mmHg) or hypotension (BP< 90/50 мм рт.ст.).

In patients with episodes of anterior non-arteritic ischemic optic neuropathy (history).

Application features

Use during pregnancy and lactation

According to the registered indication, the drug is not intended for use in women.

Application for violations of liver function

Since the excretion of sildenafil is impaired in patients with liver damage (in particular, with cirrhosis), the dose of Sildenafil should be reduced to 25 mg.

Application for violations of kidney function

With mild and moderate renal insufficiency (CC 30-80 ml / min), dose adjustment is not required, with severe renal insufficiency (CC< 30 мл/мин) - дозу силденафила следует снизить до 25 мг.

Use in children

special instructions

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

Drugs intended for the treatment of 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, therefore, before starting any therapy for erectile dysfunction, the doctor should refer the patient to a cardiovascular examination. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mmHg), or hypotension (BP< 90/50 мм рт. ст.). В клинических исследованиях показано отсутствие различий в частоте развития инфаркта миокарда (1,1 на 100 человек в год) или частоте смертности от сердечно-сосудистых заболеваний (0,3 на 100 человек в год) у пациентов, получавших препарат Силденафил, по сравнению с пациентами, получавшими плацебо.

Cardiovascular Complications

Serious cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported during post-marketing use of sildenafil for the treatment of erectile dysfunction. ), which had a temporal relationship 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 were observed shortly after sexual activity, and some of them were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish the existence of a direct relationship between the observed adverse events and these or other factors.

hypotension

Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in LD, which is not clinically significant and does not lead to any consequences in most patients. However, before prescribing Sildenafil, the physician should carefully assess the risk of possible adverse vasodilatory effects in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in rare multiple system atrophy syndrome, 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 susceptible patients, Sildenafil should be used with caution in patients taking α-blockers. To minimize the risk of postural hypotension in patients taking a-blockers, Sildenafil should only be started after stabilization of hemodynamic parameters in these patients. Consideration should also be given to reducing the initial dose of Sildenafil. The physician should inform patients about what actions to take if symptoms of postural hypotension appear.

Visual disturbances

Rare cases of the development of anterior non-arteritic ischemic optic neuropathy have been noted as a cause of deterioration or loss of vision during the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as excavation (deepening) of the optic disc, age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease, hyperlipidemia, and smoking. A causal relationship between the use of PDE5 inhibitors and the development of anterior non-arteritic ischemic optic neuropathy has not been identified. The physician should inform the patient about the increased risk of developing anterior non-arteritic ischemic optic neuropathy, if this condition has already been noted in him. In case of sudden loss of vision, patients should receive the necessary medical attention immediately. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of the functions of retinal phosphodiesterases. There are no data on the safety of Sildenafil in patients with retinitis pigmentosa, so Sildenafil should be used with caution.

Hearing disorders

Some post-marketing and clinical studies report cases of sudden worsening or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden worsening or loss of hearing. A causal relationship between the use of PDE5 inhibitors and sudden hearing impairment or hearing loss has not been established. In the event of a sudden deterioration in hearing or hearing loss while taking sildenafil, you should immediately consult your doctor.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. Data on the safety of the use of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers are not available, so Sildenafil should be used with caution in these patients. 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 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 taking a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction.

The safety and efficacy of Sildenafil in conjunction with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.

Influence on the ability to drive vehicles and control mechanisms

Against the background of taking sildenafil, no negative effect on the ability to drive a car or other technical means was observed.

However, since when taking sildenafil, a decrease in blood pressure, the development of chromatopsia, blurred vision, etc. is possible. side effects, you should carefully consider the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosing regimen.

Other factors being equal, an approximate estimate of the differences in therapeutic dosages between vardenafil and sildenafil can be made based on the differences between their biochemical potency (approximately 10 times greater for vardenafil) and bioavailability (approximately 3.3 times greater for sildenafil). In accordance with this calculation, the therapeutic dose of vardenafil should be three times less than that of sildenafil. This generally reflects the actual relationship between the highest recommended dose of vardenafil (20 mg) and . The slight difference may be due to the existence of currently unknown pharmacokinetic factors.

All three drugs have similar t values, which are in the range of 0.25-1.5 hours. The absorption of sildenafil and vardenafil slows down significantly in cases of their use after a fatty meal. Tadalafil, on the contrary, is absorbed rather slowly and does not depend on food intake and alcohol.

The C-value of vardenafil is significantly lower than that of the other two PDE-5 inhibitors.

One of the most notable differences between PDE-5 inhibitors is that tadalafil significantly outperforms the other two drugs. The reasons for this difference may be slow metabolism of the drug in the liver and, possibly, other currently unknown factors. The increased half-life provides new therapeutic options for patients who value spontaneity of sexual activity in the absence of strict time limits. In addition, the long duration of action of this drug may be important in the treatment of chronic diseases in which PDE-5 inhibitors can be used. On the other hand, in some patients, the time of action of the drug coincides with the duration of side effects.

In conclusion of this section, it should be noted that the existence on the market of three highly selective and effective PDE-5 inhibitors, sildenafil, tadalafil and used in the treatment of ED, is an outstanding result of many years of research and clinical trials. Although all three drugs are comparable in their ability to inhibit PDE-5 and selectivity in inhibiting this particular form of the enzyme, differences in potency, interaction with food and alcohol, half-lives and other characteristics make certain drugs more suitable in certain clinical situations. Currently, several research groups are developing new drugs that can selectively inhibit PDE-5 and have their own structural and pharmacokinetic features. The appearance on the market of these drugs will make the therapeutic arsenal of the andrologist even more diverse and to an even greater extent increase the number of patients satisfied with the treatment of ED.

To restore normal sexual intercourse in men and sexual desire in women, Sildenafil is used - the instructions for use also contain indications that the drug can be used as a drug with an antihypertensive effect. In pharmacies there is an original medication (Viagra) and generics. The latter are cheaper in price, but have an equal effect. Familiarize yourself with the rules for taking the medication, possible contraindications.

Sildenafil tablets

According to the instructions for use, Sildenafil is a potent vasodilator. It is used to treat male erectile dysfunction, normalize the natural response to sexual desire and arousal. In addition, the scope of the drug is the treatment of pulmonary hypertension, because it reduces pressure.

Viagra is considered the original drug containing sildenafil, and the drug in question is generic Viagra. This word is understood as a non-original medication, but made using the same technology, having a similar effect. The cost of generics is always lower, because you only need to repeat the original recipe, the patent term of which is valid for 5-10 years. The composition of generics may differ, but the dosage of the active substance is always the same.

Compound

The active ingredient in this drug is sildenafil citrate (citrate sildenafil). Its concentration in tablets can be 25, 50 and 100 mg in one piece. Other components of the composition are:

Release form

Sildenafil is presented in the form of diamond-shaped biconvex tablets, colored in light blue. They are film coated. Sold in 1, 2, 4, 10 or 20 tablets. Up to 10 pieces are packed in a blister pack, 20 pieces are packaged in a polymer jar or a polymer bottle. Each jar, bottle or blister pack is supplied with a cardboard box.

Pharmacodynamics and pharmacokinetics

The mechanism of action of Sildenafil is the use of isoenzyme inhibitors, according to the clinical effect, it is a vasodilator drug. Pills eliminate erectile dysfunction, help maintain the tension of the penis in order to have a full sexual intercourse. The active substance acts on selective inhibitors of cytochrome, CGMP enhances sexual arousal.

In the process, a large amount of nitric oxide is released, which dilates blood vessels and increases blood flow. The oxide is affected by an active metabolite, which is destroyed by substrates of the cytochrome isoenzyme: it is sildenafil citrate that affects it, prolonging the state of the dilated vessels of the penis, the duration of erection. The drug is not able to independently cause blood flow to the cavernous bodies, only increase sexual arousal. In the absence of sexual stimulation, it is ineffective. Sildenafil is metabolized by the liver.

In relation to hypertension, sildenafil citrate inhibits the activity of an enzyme that is contained in the pulmonary vessels, and not only in the tissues of the genital organs, enhances the hypotensive effect. The selective action of the drug is found in the arteries. Inhibitor pharmacokinetics: Sildenafil clearance is 41 l/h in plasma. Using the remedy, you can achieve an improvement in the quality of life, reduce shortness of breath, respiratory failure. A parallel effect of the drug is a temporary decrease in blood pressure. Sildenafil is excreted by the kidneys.

Indications for use

Sildenafil - instructions for use clearly indicate the indications for its use - a drug with proven effectiveness in:

• treatment of erectile dysfunction of the penis caused by organic, psychogenic, mixed causes - diabetes mellitus, obesity, removal of the prostate gland, spinal cord injury;
• elimination of the impossibility of maintaining the penis in a sufficiently dense state for a full-fledged sexual intercourse;
• pulmonary hypertension.

Sildenafil - how to take

According to the instructions, the tablets of the drug are taken orally, washed down with a glass of clean water. The average dosage per day is 50 mg, and the maximum is 100 mg. Reception is carried out one hour before sexual activity. It is best to take the tablets on an empty stomach. With liver damage, a low glomerular filtration rate, the dose of application is reduced to 25 mg, similarly it is reduced while taking Ritonavir. The placebo effect has been observed.

With arterial hypertension, Viagra should be taken 25 mg three times a day, observing equal intervals between doses of 6-8 hours. The maximum single dose is 50 mg, but it should be increased only if indicated and the drug is well tolerated. With poor tolerance, the dosage is reduced to 25 mg twice a day, as the instructions say.

special instructions

In the treatment of erectile dysfunction, a cardiovascular examination is performed before the appointment of Sildenafil. The drug is used with caution by patients with anatomical deformity of the penis (angulation, cavernous fibrosis), with diseases suggesting the development of priapism (sickle cell anemia, multiple myeloma, leukemia).

The drug is not used in patients who do not wish to receive sexual activity, under the age of 18 years. With caution, you can use tablets with a tendency to bleeding, gastric ulcer and duodenal ulcer during exacerbation, hereditary retinitis of pigments. The speed of psychomotor reactions does not change when taking Sildenafil.

Sildenafil for women

In addition to the treatment of men, the drug can be used in the treatment of violations of the sexual sphere of women. The effectiveness of Sildenafil was found to stimulate sexual arousal even after removal of the uterus or during menopause. The drug works on women like this:

• enhances sexual functions, increases libido, sensuality;
• reduces the time required to achieve sexual arousal;
• improves the production of vaginal lubrication, blood flow in the pelvic organs, sensations from caresses;
• prolongs orgasm, increases stamina, eliminates frigidity even in older women.

Sildenafil and alcohol

It is undesirable to combine the drug Sildenafil with alcohol, although ethyl alcohol does not directly affect the absorption of the drug. Alcohol-containing drinks and drugs reduce libido, inhibit potency, the central nervous system. When taken simultaneously with Sildenafil, the load on the liver increases, the effect of the drug may be unjustified and useless.

Interaction with drugs

Sildenafil - instructions for its use states the facts of interaction with other drugs - is used as part of complex therapy. In this case:

• the time of action is prolonged when combined with Tetracycline, Ketoconazole, Erythromycin, Saquinavir;
• in those taking nitrates, Sildenafil enhances the effect of sodium nitroprusside, nitroglycerin, nitric oxide donors, antihypertensive drugs;
• the pharmacokinetics of Ritonavir increases the pharmacokinetics of Sildenafil;
• blockers can lead to a strong decrease in blood pressure, dizziness.

Side effects and overdose

When using high doses of the drug over 800 mg, an overdose is possible, characterized by a feeling of heat, dizziness, reddening of the face, headaches, nasal congestion, pressure drop and indigestion. Clinical drugs can relieve symptoms. Side effects from the use of Sildenafil are:

• drowsiness, fainting;
• blurred vision, impaired color perception, lacrimation;
• deafness, tinnitus;
• increased heart rate, myocardial infarction, tachycardia, low blood pressure;
• vomiting, nausea;
• dry mouth, cramps, skin rash;
• ischemic attacks, arrhythmia;
• tremor, migraine, paresthesia, insomnia;
• cough, diarrhea, heartburn;
• sweating, inflammation of the subcutaneous tissue, muscle pain;
• gynecomastia, fever, swelling.

Contraindications

According to the instructions for the use of Sildenafil, the following are distinguished contraindications in which the use of the drug is prohibited:

• unstable angina;
• severe heart failure;
• aortic stenosis;
• cardiomyopathy;
• poor eyesight, congenital pathologies of the retina;
• severe liver disease;
• stroke or myocardial infarction;
• age under 18;
• hypersensitivity to components.

Terms of sale and storage

In pharmacies, Sildenafil can be bought with a prescription. The drug is stored in a dry place protected from light and children at temperatures up to 25 degrees. The shelf life is three years. Instructions for use do not recommend the use of a drug that has expired.

Sildenafil's analogs

In the pharmacy you can find generic Sildenafil and the original. Analogues of Viagra by pharmacological action and active ingredient:

• Viasan;
• Viagrande;
• Viprogra;
• Kamagra;
• capacity;
• Pemegra;
• Pfiagra;
• Silafil;
• Sildigra;
• North Star;
• Suhagra;
• Tornetis;
• Odegra;
• Levitra;
• Impaza;
• Sealex;
• Vuka-Vuka.

Sildenafil price

You can buy a drug with sildenafil on the Internet or in the usual pharmacies. The cost depends on the manufacturer, the number of tablets in the package and the concentration of the active substance. Approximate prices in Moscow.

Male potency is an important component of the health of every male body. It is the erectile function that most men put in the foreground in their lives and are very panicked if suddenly something did not work out in bed with a partner. Fortunately, modern methods and methods of treatment allow, at the first manifestations of the disease, to cure it, and right now we will talk about one drug that quickly restores male sexual dysfunction.

Sildenafil citrate, or in other words the same Viagra, is a drug that was registered at the end of the 20th century and was intended for the treatment of erectile dysfunction in the male body.

Already a few years after the registration of the named remedy, more than ten million men around the world tried this drug on themselves and 80% of them were satisfied with Sildenafil. At the same time, studies of the drug continued, and the instructions for its use began to be supplemented with new useful instructions.

Conducting additional research, scientists realized that the drug can have its therapeutic effect on the treatment of potency without side effects even on diabetics and people who have a malfunction in the cardiovascular system and spinal cord injury.

The results of a study on the use of Sildenafil citrate in patients with prostate cancer, depressed people and patients with Parkinson's disease were also encouraging. All of them showed improvements in erectile function, and no side effects were observed.

Most of the side effects that were found by specialists in the initial studies of the drug were mild or moderately severe. There were extremely rare cases when the treatment with the named remedy had to be stopped. These cases are less than 1% of all.

Pharmacological properties of Sildenafil, release form

Sildenafil citrate is available in coated tablets. The package contains one or more blisters of one tablet or four tablets on one such blister. Each package contains instructions for using the remedy that has a therapeutic effect.

Before starting treatment with Sildenafil tablets, the instructions for its use must be read. It is necessary to purchase tablets after consulting a doctor. Self-medication can lead to disastrous consequences.

Sidenafil citrate 140 mg tablets contain 100 mg of seldinafil itself.

• cellulose microcrystalline;
• lactose monohydrate;
• magnesium;
• povidone;
• indigo carmine;
• titanium dioxide.

If initially the drug was developed as a remedy for the treatment of cardiovascular diseases, today the main purpose of Sildenafil, as the instructions say, is to increase erectile function in men.

The medicine helps to restore lost sexual arousal. When taking the named drug, depending on the characteristics of the organism and the causes of the onset of the disease, the erection is restored to 100%.

Under the influence of Sildenafil, cyclic guanosine monophosphate (cGMP) breaks down, blood circulation and blood filling of the muscles of the male penis increases. In 77% of men after taking the drug, erectile dysfunction is completely restored and a representative of a strong half is able to perform a normal, full-fledged sexual intercourse.

The drug is taken 40-50 minutes before intimacy, the effect of Sildenafil lasts up to 4 hours.

Side effects and contraindications

Despite the effectiveness of the drug and the minimal side effects from taking it, such effects are still observed in some cases.

• the appearance of a headache;
• severe reddening of the face due to a rush of blood to it;
• visual impairment;
• the appearance of dyspepsia;
• congestion in the sinuses;
• skin rash;
• infections in the urinary system;
• dizziness;
• diarrhea.

In a number of cases (isolated cases) there were observed: fainting, ringing in the ears, dry mouth, tachycardia, photophobia, swelling of the genital organs, arthritis, frequent urination, thirst for water, increased sputum when coughing, and some others. Such effects were recorded when taking the drug at a dosage of 100 mg. No such side effects were observed at lower dosages.

It may be that Sildenafil is contraindicated for some individuals at all.

Medical contraindications include:

• hypersensitivity to the components of the drug;
• deformation of the penis;
• parallel treatment with nitrate preparations;
• kidney failure;
• frequent bleeding;
• cirrhosis of the liver;
• severe hypertension;
• heart disease (strokes and heart attacks);
• unstable angina;
• arrhythmia.

How to use Sildenafil and dosage

As the instructions say, Sildenafil tablets should be taken 50-60 minutes before sex.

A single dose per day for adult men is not more than 50 mg.

The dosage of the drug is prescribed only by a doctor. Do not self-medicate, remember, this can lead to disastrous consequences.

Given the patient's tolerance to the components of the drug and the individual characteristics of his body, the doctor may reduce the single dosage to 25 mg or, on the contrary, increase it to 100 mg. Only the doctor decides!

100 mg is the maximum allowable daily dosage of the drug.

For men aged 45 and older, it is not recommended to change the daily dose of 50 mg in either direction. This can lead to undesirable consequences if the dosage is increased or will not bring the desired effect if the dosage is reduced.

How to use Sildenafil in patients with renal insufficiency and is it possible to use the drug while taking other drugs?

1. In the presence of cirrhosis of the liver or renal failure of any severity, the drug can be prescribed, however, a single dose of the drug is reduced in dosage to 25 mg.
2. It is strictly forbidden to take Sildenafril in parallel with nitrates. In addition, it is recommended to reduce the dosage of the drug to 25 mg if the patient is taking CYP3A4 inhibitors (with the exception of Ritonavir, with which Sildenafril is contraindicated) and alpha-adrenergic receptor blockers.

It is forbidden to use Sildenafril citrate for persons under 18 years of age, as well as for patients over 75 years of age.

With an overdose of Sildenafil, patients experience pronounced side effects - dizziness, rash, blurred vision, blood in the urine, and others. As a rule, such effects are observed when taking more than 100 mg of the drug per day.

The higher the dosage, the greater the severity of side effects observed and it is important to remember and know this. For the treatment of overdose symptoms for men, the doctor prescribes special symptomatic therapy.

Precautions while taking Sildenafil

Before you start taking Sildenafil, it is important to consult a doctor.

The specialist, prescribing the drug, examines the patient's tests, identifies the causes that affected the sexual function of the male body, and only then prescribes the treatment.

Before prescribing a medicine, a man must undergo a general clinical and urological examination.

The drug may be contraindicated for those who, for a number of clinical (physiological) reasons, have unwanted sexual activity. These can be people with various forms of heart disease, as well as patients with kidney failure, cirrhosis of the liver, men over 70, etc.

When prescribing, the doctor takes into account not only physiological contraindications, but also contraindications for taking Sildenafil with other drugs. So, as already noted, the use of the named drug with nitrates is not recommended.

Sildenafil is not indicated for use in women, as well as in children and adolescents under the age of 18 years.

Special instructions for the use of Sildenafil

Before taking Sildenafil, as a drug that normalizes erectile dysfunction, it is important for the patient to undergo a heart examination, as well as to conduct an examination of the vascular system.

With extreme caution, Sildenafil is prescribed to men who have anatomical deformities of the penis (for example, cavernous fibrosis, etc.), as well as to people predisposed to leukemia, sickle cell anemia and multiple myeloma.

Sildenafil should not be taken by men who, for one reason or another, are contraindicated in sexual activity.

With extreme caution should be approached when taking the drug to people:

• prone to frequent bleeding;
• with duodenal disease in the process of exacerbation of the disease;
• with peptic ulcer;
• with retinitis pigmentosa.

You can not take Sildenafil citrate, even in the smallest dose, to persons under 18 years of age.

As for driving while taking the medicine, doctors note that there is no effect of the drug on drivers, and therefore Sildenafil tablets can be used by those who are going to drive.

Sildenafil's analogs

An analogue of Sildenafil citrate is any drug of the same pharmacological group, that is, a medicine that has Sildenafil in its composition and has the same medicinal property.

In the modern market of medicines, there are a huge number of analogues of Sildenafil. The most popular among them are: Viagra, Dynamico, Pemegra, Tornetis, Silafil, Viprogra, Edegra, Kamagra, etc.

The first, most famous and most effective analogue of Sildenafil is Viagra. Today, this drug to increase erectile male function can be bought at any pharmacy.

What is the main difference between analogues and originals?

1. Analogues are cheaper.
2. When developing the original, special studies, experiments are carried out, side and other effects are revealed, and only then a technique is developed for cleaning the main element from impurities, the best technique for taking the drug and its dosage. Such a drug is patented and put on the market. In the case of analogues, pharmacological companies simply use the main substance of the original drugs, supplementing them with others. The result is a new medicine with a new name (name) and already at a different price than the original.

Sildenafil Citrate for Women

Sildenafil, as doctors point out, is a purely male drug that serves to maintain and restore potency in men. Meanwhile, the properties of the main substance of the drug are able to lower the pressure in the pulmonary artery, and therefore the drug can be prescribed to people suffering from a mild form of pulmonary hypertension. It can be women, but in such cases the drug will have a slightly different name.

Sildenafil for women is available under the brand namesfemalegra,Ladygra and Womenra.

The active substance in these preparations is the same Sildenafil citrate.

When taking the medicine, women also experience some side effects.

These include:

• violation of visual function;
• nasal congestion;
• dizziness and headache;
• fear of the world.

Sildenafril citrate for the fair half not only relieves hypertension, but, as experts point out, it has the same effect as on men - the effect of restoring sexual desire.

Before taking the drug, it is important to consult a doctor.

Conclusion

Clinical studies for more than 3 years and about 10 more years of close observation of the effectiveness of the drug in humans have practically not changed the first ideas about the safety and effectiveness of Sildenafil.

Sildenafil is well tolerated by almost all groups of men, including those who have a psychogenic, organic and mixed etiology of erectile dysfunction.

Today, the drug is used all over the world, has hundreds of analogues. The tolerability of the components of the drug is good, the number of people who have experienced serious side effects from taking Sildenafil is minimal (less than 1% of all patients who have tried the drug).

Drawing conclusions

Did you have a misfire? Judging by the fact that you are reading this article, victory is not on your side.

And of course, you know firsthand that a violation of potency is:

• Low self-esteem
• Women remember your every failure, tell their girlfriends and your friends
• prostate disease
• Developing depression that negatively affects your health

Now answer the question: DOES THIS SUIT YOU? Can this be tolerated? Do you remember that feeling when you look at a naked woman and can't do anything? Enough - it's time to get rid of problems with potency, once and for all! Do you agree?

We have studied a huge amount of materials and, most importantly, tested most of the means for potency in practice. So, it turned out that a 100% working drug without any side effects is Predstanol. This drug consists of natural ingredients that completely exclude chemistry.

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