PDE-5 inhibition and sexual response: Pharmacological mechanisms and clinical outcomes

Annual Review of Sex Research, 2002 by Rosen, Raymond C, McKenna, Kevin E

Phosphodiesterase type-5 (PDE-5) inhibitors are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction (ED). The mechanism of action involves active inhibition of the PDE-5 enzyme and resulting increase in cyclic guanosine monophosphate (cGMP) and smooth muscle relaxation in the penis. Sildenafil citrate (Viagra) is a potent and selective PDE-5 inhibitor, which is the first drug in this class to be approved for treatment of ED. More than 10 million men worldwide have been treated with this drug. Sildenafil has been shown to be generally effective in the treatment of ED, although the degree of efficacy varies according to the etiology and severity of the disorder. The drug is well tolerated, with relatively few contraindications (e.g., nitrates) and safety risks. The cardiovascular effects of sildenafil, in particular, have been extensively investigated. The results of recent studies suggest that sildenafil may have an additional role in the treatment of other male and female sexual disorders, such as premature ejaculation and female sexual arousal disorder, although results to date are inconclusive. Two additional agents in this class (tadalafil [Cialis], vardenafil [Levitra]) have been developed recently and are under regulatory review. Tadalafil is a long-acting PDE-5 inhibitor, which is effective for up to 36 hr in the majority of men. Vardenafil has a similar duration of action to sildenafil, but is more potent and selective biochemically. Both drugs appear to be generally safe and well tolerated, with a similar side-effect profile to sildenafil. There are no controlled comparison studies to date. Despite the overall effectiveness of PDE-5 inhibitors in the treatment of ED, significant psychological and interpersonal issues need to be addressed in their clinical use. The potential impact on societal attitudes toward sexuality and sexual dysfunction also warrants consideration.

Key Words: erectile dysfunction, erection, female sexual dysfunction, Phosphodiesterase type-5 inhibitor, penis, sildenafil, tadalafil, vardenafil.

The office of medicine is but to tune this curious harp of man's body and reduce it to harmony.

--Francis Bacon

Chance favors the prepaired mind

--Louis Pasteur

Historically, a potpourri of potions, elixirs, and remedies have been used to enhance sexual performance or to alleviate sexual problems in men and women (Buffum, 1982; Crenshaw & Goldberg, 1996). The vast majority of these compounds have been of unproven efficacy and safety, with their popularity based on personal or cultural beliefs rather than scientific evidence. More recently, pharmacologic agents in various classes have been proposed as potential "prosexual drugs" (Foreman & Wernicke, 1990; Rosen & Ashton, 1993). These have included centrally and peripherally active agents, drugs with supposed effects on libido, sexual arousal or orgasm, and a wide array of potential therapeutic mechanisms and actions (Crenshaw & Goldberg, 1996). A particular area of focus has been the development of pharmacologic agents for treating male erectile dysfunction (ED). Development of this class of drugs has been spurred, in part, by new knowledge of the neurovascular mechanisms of erection, and the role of nonadrenergic, noncholinergic (NANC) mechanisms in particular. Conversely, the availability of newer pharmacologic agents for treating ED has contributed to basic research on the neurochemistry of erection. With increased understanding of the underlying mechanisms involved, the potential has arisen for development of highly effective and potentially well tolerated clinical treatments. The implications of these developments for managing sexual problems in men and women, and for societal attitudes toward sexuality and sexual dysfunction in general, are considerable.

The contemporary era in pharmacologic management of ED can be traced to the discovery in the early 1980s of injectable, vasoactive drugs (papaverine, phentolamine) able to produce firm and lasting erections (Brindley, 1983). These agents cause erections by stimulating rapid vasodilation and relaxation of corporal smooth muscle tissue in the penis. Despite adverse effects (e.g., pain, fibrosis) and strong psychological or interpersonal barriers (Althof & Turner, 1992), intracorporal injection therapy became widely used in the treatment of ED in the late 1980s and confirmed the clinical significance of corporal smooth muscle relaxation and vasodilation in the treatment of ED (Linet & Ogrinc, 1996). Further refinements followed, such as the use of intraurethral prostaglandin suppositories (Padma-Nathan et al., 1997), which were based on the same mechanism of action. These treatments provided an important framework of plausibility for the subsequent development of oral agents that might similarly effect relaxation of the smooth muscle tissue in the penile corpora. It was not until the mid-1990s, however, that a new class of pharmacologic agents was identified-phosphodiesterase type-5 (PDE-5) inhibitors-which would have this potential when taken orally. The discovery was largely fortuitous in that sildenafil was being investigated at the time as a potential treatment for cardiovascular disease (Katzenstein, 2001).