Sildenafil, Vardenafil, Tadalafil: Basic Mechanism of Action

For the physician interested in cardiovascular issues, PDE-5 inhibitors, now broadly used for the treatment of ED, are a highly interesting class of agents. Sildenafil, the first

available agent for treatment of ED, was initially developed to find a novel anti-anginal concept. Although its anti-anginal potency was not promising in the first clinical studies, the “side effect” of enhancing penile erections soon became the main target of further clinical research.

In several tissues, smooth muscle cells relax in response to nitric oxide (NO), which stimulates the enzyme guanylate cyclase, resulting in increased intracellular concentra-tions of cyclic guanosine monophosphate (cGMP). PDE-5, the major target of the PDE-5 inhibitors sildenafil, vardenafil, and tadalafil, catalyzes the breakdown of cGMP. There-fore, in tissues containing significant activity of PDE-5, sildenafil, vardenafil, and tadalafil potentiate smooth muscle relaxation in response to NO by preventing the breakdown of cGMP. Enhanced vasodilation of the vasculature in the corpus cavernosum results in improved erection. However, there is also PDE-5 activity in the systemic arteries and veins as well as in the pulmonary circulation. PDE-5 is also present in platelets.

Therefore, the spectrum of effects and side effects of PDE-5 inhibitors in the cardiovas-cular system may be largely explained by its mechanism of action, the tissue distribution of PDE-5, and potentially on the basis of nonspecific effects on other PDE systems.