Cialis (Site and Mechanism of Action)
Tadalafil is a selective inhibitor of the enzyme phosphodiesterase type
5 (PDE5), one of a family of 11 PDEs that degrade cyclic guanosine monophosphate
(cGMP) and/or cyclic adenosine monophosphate (cAMP).
Compared with other agents in the class of PDE5 inhibitors, tadalafil has
a unique chemical structure.
Tadalafil is also considered to be highly selective for PDE5 and is more
selective for PDE5 than for any other PDEs . For example, tadalafil
is more than 10,000-fold more potent for PDE5 than for PDE1, PDE2,
PDE4, and PDE7 enzymes, which are found in the 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
PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme
found in human skeletal muscle. The physiological role and clinical relevance
of PDE11 inhibition in humans, however, have not been determined.
PDE5 is found in high concentrations in the corpus cavernosum of
the penis and, to a lesser extent, in 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 clinical
trials in patients receiving the drug. Inhibition of PDE6 is thought to
underlie the visual disturbances sometimes reported by patients taking
PDE5 inhibitors, such as sildenafil.
The mechanism by which tadalafil inhibits PDE5 and improves erections
in men with ED requires an understanding of the physiology of the erectile
response to sexual stimulation. During sexual stimulation, nitric oxide
(NO) released from nonadrenergic, noncholinergic (NANC) 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.
Tadalafil augments this naturally occurring NO-cGMP pathway by
inhibiting PDE5-induced cGMP degradation, thereby increasing levels
of cGMP and ultimately enhancing erectile function. This has been
demonstrated in vitro using tissue taken from men with ED undergoing
surgery for penile implantation. Consistent with increased cGMP
levels, tadalafil, like other PDE5 inhibitors, also enhances sodium nitroprusside
(SNP)-induced relaxation of corpus cavernosum and penile
arterial tissues, as well as relaxation induced by NO stimulation and by
acetylcholine. 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.
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