indication

Used for the treatment of erectile dysfunction.

pharmacology

Tadalafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erection involves the release of nitric oxide (NO) in the corpus cavernosum. This then activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum, resulting in increased inflow of blood and an erection. Tadalafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with tadalafil on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, tadalafil should not cause an erection.

mechanism of action

Tadalafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP 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) by tadalafil enhances erectile function by increasing the amount of cGMP.

toxicity

Oral, Rat LD₅₀ = 2000 mg/kg, no deaths or toxicity.

biotransformation

Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. In vitro data suggests the metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

absorption

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.

half life

17.5 hours

route of elimination

Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

drug interactions

Alfuzosin: Tadalafil may enhance the hypotensive effect of Alfusozin. Monitor for hypotension during concomitant therapy.

Amprenavir: Amprenavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Atazanavir: Atazanavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Clarithromycin: Clarithromycin may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Conivaptan: Conivaptan may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Darunavir: Darunavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Delavirdine: Delavirdine may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Doxazosin: Tadalafil may enhance the hypotensive effect of Doxazosin. Monitor for hypotension during concomitant therapy.

Fosamprenavir: Fosamprenavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Imatinib: Imatinib may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Indinavir: Indinavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Isoniazid: Isoniazid may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Isosorbide Dinitrate: The vasodilatory effects of Isosorbide dinitrate may be increased by Tadalafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Isosorbide Mononitrate: The vasodilatory effects of Isosobide mononitrate may be increased by Tadalafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Itraconazole: Itraconazole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Ketoconazole: Ketoconazole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Lopinavir: Lopinavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Miconazole: Miconazole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Nefazodone: Nefazodone may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Nelfinavir: Nelfinavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Nicardipine: Nicardipine may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Nitroglycerin: The vasodilatory effects of Nitroglycerin may be increased by Tadalafil. Severe hypotension may occur. Concomitant therapy is contraindicated.

Phenoxybenzamine: Tadalafil may enhance the hypotensive effect of Phenoxybenzamine. Monitor for hypotension during concomitant therapy.

Phentolamine: Tadalafil may enhance the hypotensive effect of Phentolamine. Monitor for hypotension during concomitant therapy.

Posaconazole: Posaconzole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Prazosin: Tadalafil may enhance the hypotensive effect of Prazosin. Monitor for hypotension during concomitant therapy.

Quinidine: Quinidine may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Rifampin: Rifampin may reduce Tadalafil plasma concentrations and efficacy.

Ritonavir: Ritonavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Saquinavir: Saquinavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamsulosin: Tadalafil may enhance the hypotensive effect of Tamsulosin. Monitor for hypotension during concomitant therapy.

Telithromycin: Telithromycin may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Terazosin: Tadalafil may enhance the hypotensive effect of Terazosin. Monitor for hypotension during concomitant therapy.

Tipranavir: Tipranavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of tadalafil by decreasing its metabolism. Concomitant therapy should be avoided if possible due to high risk of tadalafil toxicity.