An agent for the treatment of erectile dysfunction, is a reversible selective inhibitor of specific PDE5 cGMP. When sexual arousal induces local release of nitric oxide, inhibition of PDE5 by tadalafil results in an increase in cGMP levels in the corpus cavernosum of the penis. The consequence is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil is ineffective in the absence of sexual stimulation.
In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, in the smooth muscles of the vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs, and cerebellum. The effect of tadalafil on PDE5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more active against PDE5 than against PDE1, PDE2, PDE4, which are localized in the heart, brain, blood vessels, liver and other organs. Tadalafil is 10,000 times more active in blocking PDE5 than PDE3, an enzyme found in the heart and blood vessels.
This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in the contraction of the heart muscle. In addition, tadalafil is approximately 700 times more active against PDE5 than against PDE6, which is found in the retina and is responsible for phototransmission. Tadalafil is also 10,000 times more active against PDE5 compared to its effect on PDE7-PDE10.
Acts within 36 hours. The effect appears within 16 minutes after ingestion in the presence of sexual arousal.
Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic pressure, compared with placebo in the supine position (the average maximum decrease is 1.6 / 0.8 mm Hg, respectively) and standing (the average maximum decrease is 0.2 / 4.6 mm Hg. respectively). Tadalafil does not cause a significant change in heart rate.
Tadalafil does not cause changes in color recognition (blue / green), which is explained by its low affinity for PDE6. In addition, no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size was noted.
There was no clinically significant effect on sperm characteristics in men who took tadalafil in daily doses for 6 months.
After oral administration, tadalafil is rapidly absorbed. Cmax is reached on average after 2 hours. The rate and degree of absorption do not depend on food intake. The pharmacokinetics of tadalafil in healthy individuals is linear with respect to time and dose. In the dose range from 2.5 to 20 mg, AUC increases in proportion to the dose. Css in plasma is reached within 5 days when taking the drug 1 time / day.
The pharmacokinetics of tadalafil in patients with erectile dysfunction is similar to the pharmacokinetics of the drug in persons without erectile dysfunction.Vd is about 63 L, which indicates that tadalafil is distributed in body tissues. At therapeutic concentrations, 94% of tadalafil binds to plasma proteins. In healthy individuals, less than 0.0005% of the administered dose is found in semen.Metabolized with the participation of the isoenzyme CYP3A4. The main circulating metabolite is methylcatechol glucuronide, which is 13,000 times less active against PDE5 than tadalafil, so it is unlikely that this metabolite is clinically significant.In healthy individuals, the average clearance of tadalafil when taken orally is 2.5 l / h, and the average T1 / 2 is 17.5 hours.Tadalafil is excreted mainly in the form of inactive metabolites, mainly in the feces (about 61%) and to a lesser extent in the urine (about 36 %).In patients with mild renal insufficiency (CC from 51 to 80 ml / min) or moderate (CC from 31 to 50 ml / min) AUC is higher than in healthy individuals.
Simultaneous administration of drugs containing any organic nitrates; children and adolescents up to 18 years old; hypersensitivity to tadalafil.
Pregnancy and lactation
The drug is not used in women.
Most often: headache, dyspepsia.
Possibly: back pain, myalgia, nasal congestion, flushing of the face.
Rarely: eyelid edema, eye pain, conjunctival hyperemia, dizziness.
Tadalafil is mainly metabolized with the participation of the CYP3A4 enzyme. The selective inhibitor of CYP3A4 ketoconazole increases AUC by 107%, and rifampicin reduces it by 88%.
Despite the fact that specific interactions have not been studied, it can be assumed that protease inhibitors such as ritonavir and saquinavir, as well as CYP3A4 inhibitors such as erythromycin and itraconazole, increase the activity of tadalafil.
With the simultaneous administration of an antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil, the rate of absorption of the latter decreases without changing its AUC.
Tadalafil enhances the hypotensive effect of nitrates. This is due to the additive effect of nitrates and tadalafil on the metabolism of nitric oxide and cGMP. Therefore, the use of tadalafil in patients receiving nitrates is contraindicated.
Dosage and administration
The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the used dosage form of a specific drug with indications for use and dosage regimen should be strictly observed.Middle-aged men are advised to take 20 mg at least 16 minutes before expected sexual activity, regardless of food intake. Patients can attempt intercourse at any time within 36 hours after ingestion in order to establish the optimal response time to taking tadalafil. The maximum frequency of admission is 1 time / day.
With extreme caution and only if absolutely necessary, it is possible to use tadalafil in patients with severe renal insufficiency (CC≤30 ml / min) and severe hepatic insufficiency.
During treatment with tadalafil, patients with moderate renal insufficiency (CC from 31 to 50 ml / min) were more likely to have back pain compared with patients with mild renal insufficiency (CC from 51 to 80 ml / min) or healthy volunteers ... In patients with CC ≤50 ml / min, tadalafil should be used with caution.
Therefore, the treatment of erectile dysfunction, incl. with the use of tadalafil should not be carried out in men with heart diseases in which sexual activity is not recommended.
Consideration should be given to the potential risk of complications during sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days; unstable angina or angina that occurs during intercourse; chronic heart failure (functional class II and higher according to the NYHA classification), which has developed within the last 6 months; uncontrolled heart rhythm disturbances; arterial hypotension (blood pressure less than 90/50 mm Hg) or uncontrolled arterial hypertension; a stroke in the past 6 months.Tadalafil should be used with caution in patients with a predisposition to priapism (for example, with sickle cell anemia, multiple myeloma or leukemia) or in patients with anatomical deformity of the penis (for example, with angulation, cavernous fibrosis or Peyronie's disease).
The patient should be informed of the need for immediate medical attention in case of an erection lasting 4 hours or more. Untimely treatment of priapism leads to damage to the tissues of the penis, as a result of which a long-term loss of potency may occur.No cases of priapism have been reported with tadalafil.
It is not recommended to use tadalafil in combination with other treatments for erectile dysfunction.