Oral Agents


A) PDE5 inhibitors

Sildenafil
Sildenafil was originally developed for heart disease, but was found to have a unique mechanism of action that targeted only factors in the penis, even though it is taken orally. Sildenafil is the first orally administered treatment of proven efficacy for erectile dysfunction. Taken for one hour before planned sexual intercourse, it is effective for a wide range of disorders causing erectile dysfunction.

The rationale for the use of sildenafil is based upon the role of nitric oxide-induced vasodilation (which is mediated by cyclic GMP) in initiating and maintaining an erection. Detumescence is associated with catabolism of cyclic GMP by type 5 cyclic GMP phosphodiesterase. Sildenafil acts by blocking the latter enzyme and as a result increases both the number and duration of erections in men with erectile dysfunction.

In order to understand the action of sildenafil as well as some of its side effects, it would be worthwhile to briefly recall the physiology of penile erection.

Physiology of Penile Erection
With sexual arousal through imaginative, visual, auditory, tactile, olfactory, and other erotic stimuli, nitric oxide (NO) is released by nonadrenergic, noncholinergic (NANC) neurons. Originally termed endothelial-derived relaxing factor, NO is known to be the most important physiologically occurring vasoactive molecule in the entire cardiovascular system. This also applies to corpus cavernosum function, where local smooth muscle relaxation, and in turn erection, is mediated predominantly by NO release.

Dilation of the helicine arterioles and relaxation of the sinusoids lead to engorgement of sinusoidal spaces with blood. Expansion against the tunica albuginea compresses blood-draining subtunical venules, resulting in blockade of cavernous venous outflow. This leads to complete filling of the cavernous sinusoids and subsequently to a considerable increase of the intracavernous pressure. In the phase of full rigidity, intracavernous pressure reaches values considerably higher than systemic (systolic) blood pressure.During male sexual arousal, NO is released either at parasympathetic NANC nerve terminals on the cavernous smooth muscle cell or at parasympathetic cholinergic nerve terminals on the endothelial cell lining of the sinusoids. Through membrane-bound G proteins, NO activates guanylate cyclase, which induces cleavage of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate (3',5'-cGMP).The smooth muscle-relaxing effects of NO are mediated by this second messenger (cGMP). Cyclic GMP activates protein kinase G (PKG), which phosphorylates proteins at the so-called maxi-potassium channels. This results in an outflow of potassium (K+) ions into the extracellular space with subsequent hyperpolarization, with inhibition or blockade of voltage-dependent calcium (Ca++) channels and therefore a decrease in intracellular Ca++ ion concentrations.


Relaxation of Penile Smooth Muscle via cGMP Pathway

The intracellular decline in Ca++ ions suppresses the activity of myosin light chain (MLC) kinase and thus increases the intracellular content of dephosphorylated MLC, which enables the smooth muscle cell to relax. It is well established that NO and cGMP are the most important transmitters for onset and maintenance of erection.

A simpler biochemical cascade is seen below. Although some events in the cascade resulting in penile erection await clarification, NO, a gas with intrinsic vasodilator properties, activates guanylate cyclase and in turn stimulates the formation of cGMP This substance then acts as a second messenger, playing a pivotal role in vasodilatation and relaxation of corporal smooth muscle, the structural changes responsible for penile erection.

For detumescence to take place, the raised levels of cGMP have to be lowered. PDE5 and, to a much lesser extent, PDE2 and PDE3, are localized to the corpus cavernosum of the penis, where they catalyze the transformation of cGMP to its inactive form 5_-GMP. The breakdown of cGMP reverses the erectile process, restoring the penis to its flaccid state.

The PDEs are responsible for enzymatic degradation of the biologically active cGMP and cAMP to the biological inactive molecules GMP and AMP. By inhibiting the degradation of cGMP, PDE5 inhibitors prolong the activity of this cyclic nucleotide second messenger within the cavernous vasculature and smooth musculature, thus potentiating the erectile response.

smooth musculature, thus potentiating the erectile response.
PDE5 inhibition and the response to sexual stimulation. cGMP, cyclic guanosine monophosphate; GTP, guanosine 5'-triphosphate; PDE5, phosphodiesterase 5

The prototype of this new class of selective PDE5 inhibitors for the treatment of ED was sildenafil.