Section IV: Novel therapies for the treatment of erectile dysfunction Content Points: Oral medications now represent first-line therapy, with sildenafil the current drug of choice.41 Penile injection therapy (with alprostadil) is a good choice for men in whom sildenafil is contraindicated. Alprostadil causes smooth muscle relaxation, inducing erection without the need for neural input. Intraurethral administration also uses alprostadil, but in pellet form; success depends on vascular communication between the corpus spongiosum enclosing the urethra and the corpus cavernosa. Vacuum constrictive devices draw blood into the penis to cause rigidity. A band placed around the base of the penis maintains erection. Like penile injection therapy, this procedure is a good choice when sildenafil cannot be used. Penile prostheses require a minor surgical procedure, but have advantages in ease of use and reliability. They rank high on the satisfaction scale for ED when oral therapy cannot be used. Arterial bypass procedures are used in selective cases of young men with traumatic injuries to the penile arteries. Testosterone supplementation is used if serum concentrations of total or free testosterone are low or low normal. Forms of testosterone supplementation include topical patches, intramuscular depot injections, and oral administration.

Chemical structures of PDE5 inhibitors vs cGMP Content Points: As shown, PDE5 inhibitors have structures similar to cGMP.

Selectivity of sildenafil for PDE1-6 Content Points: The relative selectivity of sildenafil for PDE5 was measured by IC50 determinations. Inhibition of PDE activity was expressed as percent of mean control activity (percent turnover of substrate).42 The results show that at clinical doses, sildenafil is unlikely to have any effect on processes mediated by PDE1-4. The 10-fold selectivity for PDE6 may explain the transient visual disturbances reported at higher doses.

Selectivity of sildenafil for PDE7-11 Content Points: The selectivity of sildenafil for PDE7-11 was determined as for PDE1-6, described on the previous slide.42 Sildenafil is unlikely to affect processes mediated by PDE7-11.

Cellular localization of PDE11 and the contribution of PDE11 inhibition to nerve-stimulated relaxation Content Points: PDE11 has been found in human vascular smooth muscle, cardiac myocytes,43 and human corpus cavernosum.44 PDE11 is closely related to PDE5. However, PDE11 is not inhibited by sildenafil.42 A combined PDE5/PDE11 inhibitor gives no additional relaxation response over a selective PDE5 inhibitor in vitro.44 Thus, no additional vasodilation is achieved by PDE11 inhibition. The physiologic role of PDE11 requires further investigation.

Pharmacokinetics of PDE5 inhibitors Content Points: The pharmacokinetics of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil vary.45-47 Tadalafil is the longest acting. The clinical significance of this is unclear, since only sildenafil has been marketed and widely used.

Pharmacokinetics of PDE5 inhibitors (cont'd) Content Points: All three PDE5 inhibitors are metabolized hepatically. Only sildenafil has an active metabolite.