Saturday, December 11, 2010


Tadalafil is a selective inhibitor of the enzyme phosphodiesterase type 5 (PDE5), one of a family of I I PDEs that degrade cyclic guanosine mono-phosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP). Compared with other agents in the class of PDE5 inhibitors, tadalafil has a unique chemical structure (Fig. 1).
Tadalafil is also considered to be highly selective for PDE5 and is more selective for PDE5 than for any other PDEs (3-5). For example, tadalafil is more than 10,000-fold more potent for PDE5 than for PDE I, PDE2, PDE4, and PDE7 enzymes, which are found in (lie heart. brain, blood vessels, liver, leukocytes, skeletal Muscles, and other organs. In addition, tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and PDE 10 and 14-fold more potent for PDE5 than for PDE I I A 1, an enzyme found in humanskeletal muscle. The physiological role and clinical rel­evance of PDEI I inhibition in humans, however. have not been deter­mined (4-6).
PDE5 is found in high concentrations in the corpus cavernosum of the penis and, to a lesser extent, i n vascular smooth muscle cells. Because PDEs are found in a variety of tissues and are implicated in a broad range Of cellular functions, the selectivity for PDE5 over other PDEs may have clinical relevance for adverse events. For example, tadalafil is a
weak inhibitor of PDE6, which is found in high concentrations only in the photoreceptors of the retina. This lower affinity of tadalafil for PDE6 may explain the low incidence of visual adverse effects reported in clini‑
cal trials in patients receiving the drug. Inhibition of PDE6 is thought to C     Z~
underlie the visual disturbances sometimes reported by patients taking PDE5 inhibitors, such as sildenafil (7).
The mechanism by which tadalafil i i bits PDE5 and improves erections in men with ED requires all understanding of the physiology of the erectile response to sexual stimulation (8,9). During sexual stimulation, Ll lation, nitric oxide (NO) released from nonadrenergic, noncholinergic (NANO) neurons and endothelial cells stimulates guanylate cyclase to produce cGMP, which in turn decreases intracellular calcium levels. This ultimately results in the relaxation of the vascular smooth muscle and increased blood flow into the corpus cavernosa, followed by penile erection (8,9).
Tadalafil augments this naturally occurring NO-cGMP pathway by inhibitim, PDE5-induced cGMP degradation, thereby increasing levels of c(;MP and ultimately enhancing erectile function (4). This has been demonstrated in vitro using tissue taken from men with ED undergoing surgery for penile implantation (3). Consistent with increased cGMP levels, tadalahl, like other PDE5 inhibitors, also enhancesWdil.1111 nitro­prusside (SNP)-induced relaxation of corpus cavernosurn and penile arterial tissues, as well as relaxation induced by NO stimulation and by acetylcholine (10). In vivo, this process results in penile erection in the presence of sexual stimulation. Because sexual stimulation is required to initiate the local release of NO, the inhibition of PDE5 has no effect in the absence of sexual stimulation (5,9).