Tadalafil Mechanism of Action

Mechanism of Action

• 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.

Pharmacodynamic Effects

• 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.

Pharmacokinetic Properties

• 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.

Biotransformation and Elimination

• 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).

Special Populations

• 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.