PDE-5 inhibitor

# Overview
A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a drug used to block the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. These drugs are used in the treatment of erectile dysfunction and were the first effective oral treatment available for the condition. Because PDE5 is also present in the arterial wall smooth muscle within the lungs, PDE5 inhibitors have also been explored for the treatment of pulmonary hypertension, a disease in which blood vessels in the lungs become overloaded with fluid, usually as a result of failure of the right ventricle of the heart.

# Indications
PDE5 inhibitors such as Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are clinically indicated for the treatment of erectile dysfunction. Sildenafil and tadalafil are also indicated for the treatment of pulmonary hypertension.
Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment for angina. Studies in 2002 explored its potential for increasing neurogenesis after stroke.

# Contraindications
PDE5 inhibitors are contraindicated in those taking nitrate medication. They are also contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors.

# Adverse reactions
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.
In 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.
Since 2007 there is evidence that PDE5 inhibitors can cause an anterior optic neuropathy.
Other ADRs and their incidence vary with the agent and are listed in their individual pages.

# Drug interactions
PDE5 inhibitors are primarily metabolized by the cytochrome P450 enzyme CYP3A4. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitors, ketoconazole, and itraconazole. Combination with NO-releasing drugs such as glyceryl trinitrate (nitro-spray) is contraindicated because potentially life-threatening hypotension (low blood pressure) may occur.

# Examples
Sildenafil was the prototypical member of the PDE5 inhibitors. Two other agents, with their own advantages/disadvantages, are also available, and several others are in development.
- avanafil
- lodenafil
- mirodenafil
- sildenafil
- tadalafil
- vardenafil
- udenafil
- zaprinast
- T-1032 made by Yanabe Seiyaku
While these drugs preferentially inhibit PDE5, none of them are truly selective, especially at high doses. Sildenafil also inhibits PDE6 and PDE9, with inhibition of PDE6 in the retina thought to be responsible for the vision changes which can be a side effect of the drug. Similarly tadalafil inhibits both PDE5 and PDE11. However the selectivity of the existing drugs is high enough that inhibition of additional PDE subtypes is not generally a problem in clinical use, and while newer "super-selective" PDE5 inhibitors have been developed for research purposes, it is unlikely any of these will be marketed given the saturation of the erectile dysfunction market at present.
Inhibitors derived from plants are also known. For example, icariin and its synthetic derivatives have been found to be PDE5 inhibitors.

# Mechanism of action
Part of the physiological process of erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased blood flow and an erection.
PDE5 inhibitors inhibit the degradation of cGMP by PDE5, increasing bloodflow to the penis during sexual stimulation.  This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.

# Notes
-  Fouad R. Kandeel. "Treatment of Erectile Dsyfunction in Men with Heart Disease". Male Sexual Dysfunction: Pathophysiology and Treatment. CRC Press, 2013. p. 453..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
-  Zhang, R.; Wang, Y; Zhang, L; Zhang, Z; Tsang, W; Lu, M; Zhang, L; Chopp, M (2002). "Sildenafil (Viagra) Induces Neurogenesis and Promotes Functional Recovery After Stroke in Rats". Stroke. 33 (11): 267580. doi:10.1161/01.STR.0000034399.95249.59. PMID 12411660.
-  Jump up to: 3.0 3.1 3.2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.Template:Pn
-  "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. Retrieved 2011-10-30.
-  Rao, Amrith R.; Thwaini, Ali; Ahmed, Hashim U.; Shergill, Iqbal S.; Minhas, Suks (2007). "The Phosphodiesterase Inhibitors and Non-Arteritic Anterior Ischaemic Optic Neuropathy: Increased Vigilance is Necessary". BJU International. 100 (1): 34. doi:10.1111/j.1464-410X.2007.06839.x. PMID 17488310.
-  Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Osterreichischer Apothekerverlag. ISBN 3-85200-196-X.CS1 maint: Unrecognized language (link)
-  Jiang, Zhaojian; Hu, Benrong; Wang, Jialing; Tang, Qiang; Tan, Yan; Xiang, Jizhou; Liu, Juyan (2006). "Effect of icariin on cyclic GMP levels and on the mRNA expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in penile cavernosum". Journal of Huazhong University of Science and Technology. 26 (4): 4602. doi:10.1007/s11596-006-0421-y. PMID 17120748.
-  Ning, Hongxiu; Xin, Zhong-Cheng; Lin, Guiting; Banie, Lia; Lue, Tom F.; Lin, Ching-Shwun (2006). "Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells". Urology. 68 (6): 13504. doi:10.1016/j.urology.2006.09.031. PMID 17169663.
-  DellAgli, Mario; Galli, Germana V.; Dal Cero, Esther; Belluti, Federica; Matera, Riccardo; Zironi, Elisa; Pagliuca, Giampiero; Bosisio, Enrica (2008). "Potent Inhibition of Human Phosphodiesterase-5 by Icariin Derivatives". Journal of Natural Products. 71 (9): 15137. doi:10.1021/np800049y. PMID 18778098.