Tadalafil Mechanism of Action

Study Notes

Tadalafil improves erectile function by increasing blood flow to the penis in response to sexual stimulation.
It does so by inhibiting phosphodiesterase type 5 (PDE5), leading to increased levels of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum.
This results in smooth muscle relaxation and increased blood flow into the penile tissues, producing an erection.

Tadalafil is a selective inhibitor of PDE5, which is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum.
It is approximately 700-fold more potent for PDE5 than for PDE6, and >10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Tadalafil is well absorbed after oral administration, with a median time to maximum observed plasma concentration (Cmax) of 2 hours after dosing.
Food and time of dosing do not affect the rate and extent of absorption.
The mean volume of distribution is approximately 63 L, and 94% of tadalafil in plasma is bound to proteins.

Tadalafil is metabolized by cytochrome P450 CYP3A4, with the major circulating metabolite being the methylcatechol glucuronide.
The metabolite is at least 13,000-fold less potent than tadalafil for PDE5.
The mean half-life is 17.5 hours in healthy subjects, and tadalafil is excreted predominantly as metabolites, mainly in the feces (61% of the dose) and to a lesser extent in the urine (36% of the dose).

Elderly patients (65 years or over) have a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years.
Patients with mild or moderate renal impairment have higher tadalafil exposure (AUC) than healthy subjects.
Patients with mild and moderate hepatic impairment (Child-Pugh Class A and B) have comparable exposure to healthy subjects, and no dose adjustment is required.
Patients with diabetes have approximately 19% lower tadalafil exposure (AUC) than healthy subjects, but this difference does not warrant a dose adjustment.