Caliberi Mechanism of Action

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.
Benign prostatic hyperplasia: The exact mechanism of action of tadalafil in benign prostatic hyperplasia is not known, tadalafil selectively inhibits phosphodiesterase type 5 (PDE5) and increases cyclic guanosine monophosphate (cGMP) levels. The smooth muscle cells of the prostate, bladder and surrounding vasculature also contain PDE5; inhibiting PDE5 and increasing cGMP levels in these tissues may cause smooth muscle relaxation, as observed in the corpus cavernosum and pulmonary arteries.
Erectile dysfunction: Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosum smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic guanosine monophosphate (GMP) in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cyclic GMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.
Pulmonary hypertension: The inhibition of phosphodiesterase type 5 (PDE5) by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.
Pharmacokinetics: Tadalafil is well absorbed after an oral dose.
Tadalafil is widely distributed into tissues and is about 94% bound to plasma proteins. It is metabolized liver mainly by the cytochrome P450 isoenzyme CYP3A4. The major metabolite, the methylcatechol glucuronide, is inactive. The mean half-life of tadalafil is about 17.5 hours.
Tadalafil is excreted, mainly as metabolites, in the feces (61 % of the dose), and to a lesser extent in the urine (36% of the dose). Clearance may be reduced in the elderly and in patients with renal impairment.