Pharmacological properties the active substance of the drug Cialis — tadalafil — is a reversible selective inhibitor of specific PDE type 5 (PDE-5) cGMP. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE-5 by tadalafil leads to an increase in the level of cGMP in the cavernous body of the penis. The consequence of this is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual stimulation. In vitro studies sildenafil 100mg have established that tadalafil is a selective inhibitor of PDE—5. PDE-5 is an enzyme detected in smooth muscles of the cavernous body and vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. The effect of tadalafil on PDE-5 is 10,000 times greater than its effect on other types of PDE (PDE-1, PDE-2, PDE-4 and PDE-7). Tadalafil blocks PDE-5 10,000 times more actively than PDE-3, an enzyme that is detected in the heart and blood vessels. This selectivity in relation to PDE-5 compared to PDE-3 is important because PDE-3 is an enzyme involved in cardiac muscle contraction. In addition, tadalafil is approximately 700 times more active against PDE-5 than against PDE-6, an enzyme detected in the retina and responsible for phototransduction.
Tadalafil also exhibits 9,000 times more potent action against PDE-5, compared with its effect on PDE-8, PDE-9 and PDE-10, as well as 14 times more potent than PDE-11. Tissue distribution and physiological effects of PDE-8 and PDE-11 were not determined. Tadalafil does not affect the perception of colors (blue/green), which is explained by its low affinity for PDE-6 compared to PDE-5. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size. For tablets of 2.5 mg, 5 mg: in all studies, rarely (<0.1%) a change in color perception was reported. Three clinical studies were conducted with the participation of 1504 patients in order to identify the period of onset of the effect of the drug Cialis, which demonstrated a statistically confirmed improvement in erectile function. Cialis works for 36 hours. The effect is manifested already 16 minutes after taking the dose in the presence of sexual arousal. Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic blood pressure compared with placebo in the supine position (the average maximum decrease is 1.6/0.8 mmHg) and in the standing position (the average maximum decrease is 0.2/4.6 mmHg). Tadalafil does not cause a significant change in heart rate. Significant changes were observed in patients who also took nitrates. A placebo-controlled study of the tadalafil effect on spermatogenesis of taking tadalafil for 6 months did not reveal a clinically significant effect of the drug on sperm characteristics (number, motility and structure of spermatozoa). For tablets of 2.5 mg, 5 mg: taking tadalafil had no effect on the level of testosterone, LH and FSH in the blood.
Tadalafil at doses of 2.5 mg and 5 mg at a dose of 1 time per day was evaluated in 3 clinical trials, which included 853 patients of different ages (from 21 to 82 years) and ethnic group, with erectile dysfunction of different degrees of severity (mild, moderate, severe) and of different etiology. Most patients have previously taken PDE-5 inhibitors if necessary. In 2 primary efficacy studies, the success rate was 57 and 67% for Cialis 5 mg, 50% for Cialis 2.5 mg compared with 31 and 37% for placebo. In studies in patients with secondary erectile dysfunction in relation to diabetes, the success rate was 41 and 46% for Cialis 5 mg and 2.5 mg, respectively, compared with 28% for placebo. Pharmacokinetics. Suction. After oral administration, tadalafil is rapidly absorbed. The average Cmax in blood plasma is reached on average 2 hours after ingestion. The rate and degree of absorption of tadalafil do not depend on food intake, so the drug can be taken regardless of food. The time of intake (morning or evening) has no significant effect on the rate and degree of absorption. Distribution. The average volume of distribution is about 63 liters. In therapeutic concentrations, 94% of tadalafil binds to plasma proteins. In healthy individuals, <0.0005% of the administered dose is detected in semen. Metabolism. Tadalafil is mainly metabolized with the participation of cytochrome P450 CYP 3A4 isoenzyme. The main circulating metabolite is methylcatecholglucuronide. This metabolite is 13,000 times less active against PDE-5 than tadalafil. Therefore, it can be assumed that this metabolite is not clinically significant in the determined concentrations. Withdrawal. In healthy individuals, the average half—life is 17.5 hours.
Tadalafil is excreted mainly in the form of inactive metabolites, mainly with feces (about 61% of the dose) and to a lesser extent with urine (about 36% of the dose). Tablets of 2.5 mg and 5 mg, the clearance of oral tadalafil is 2.5 l / h. The pharmacokinetics of tadalafil in healthy subjects is linearly proportional to time and dose. Increasing the dose from 2.5 mg to 20 mg, the exposure (AUC) increases proportionally to the dose. A constant concentration in the blood plasma is achieved for 5 days after a single dose. The pharmacokinetics of the drug is the same in patients with and without erectile dysfunction. Separate groups of patients. In healthy elderly persons (≥65 years) there was a lower clearance of tadalafil when taking the drug orally, which was expressed in an increase in AUC by 25% compared with the indicator in healthy individuals aged 19-45 years. This difference is not clinically significant and does not require dose adjustment. Kidney failure. For tablets of 2.5 mg and 5 mg: in studies using a single dose of tadalafil (5-20 mg), the AUC exposure of tadalafil almost doubled in subjects with mild (creatinine clearance — from 51 to 80 ml/min) or moderate (creatinine clearance — from 31 to 50 ml/min) renal insufficiency, also in subjects with the last stage of renal disease on dialysis.
For 20 mg tablets: in subjects with renal insufficiency, including patients on hemodialysis, the AUC exposure of tadalafil was higher than in healthy subjects. Liver failure. The exposure of tadalafil (by AUC value) in patients with mild to moderate hepatic insufficiency is comparable to that in healthy individuals. There are no data on the pharmacokinetics of tadalafil in severe hepatic insufficiency. In patients with diabetes mellitus on the background of the use of tadalafil, its exposure (AUC) was approximately 19% less than the AUC value in healthy individuals. This difference in exposure does not require dose adjustment. Indications Cialis treatment for erectile dysfunction. The drug is effective in the presence of sexual stimulation. The use of Cialis is taken orally by adults (men), regardless of food intake. Tablets of 2.5 mg and 5 mg of the drug should be taken at least 30 minutes before the alleged sexual activity.
The effectiveness of tadalafil can be maintained for 36 hours after taking the drug. Adult men: the usual recommended dose is 10 mg. In patients in whom tadalafil at a dose of 10 mg does not give an adequate effect, it is advisable to use 20 mg. The maximum recommended frequency of admission is 1 time per day. Tadalafil at a dose of 10 mg and 20 mg is prescribed for use before intended sexual activity and is not recommended for continuous daily use. In patients planning frequent use of Cialis (at least 2 times a week), it may be advisable to take the drug daily at a low dose, based on the patient's choice and the doctor's decision. For daily use, the recommended dose is 5 mg / day at approximately the same time. The dose can be reduced to 2.5 mg once a day, depending on individual tolerability. The expediency of prolonged daily use should be periodically reassessed. Elderly patients. No dosage adjustment is required. Patients with impaired renal function. In patients with mild or moderate renal impairment, no dosage adjustment is required. For patients with severe renal insufficiency, the maximum recommended dose is 10 mg, daily use is not recommended.