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March 26, 2016
Table of Contents

1 Introduction
CGMP specific phosphodiesterase type 5

Wikipedia

 

lowercase|title=cGMP specific phosphodiesterase type 5

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cGMP specific phosphodiesterase type 5 is an enzyme (EC number|3.1.4.17) from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina.

The phosphodiesterase (PDE) isozymes found in rod and cone photoreceptor cells of the retina belong to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP hydrolysis.

The interest in PDEs as molecular targets of drug action has grown with the development of isozyme-selective PDE inhibitors that offer potent inhibition of selected isozymes without the side effects attributed to nonselective inhibitors such as theophylline.

A PDE5 inhibitor that is significantly more potent and selective than zaprinast (an early PDE5 inhibitor) and comparable in its PDE inhibitory properties to sildenafil (Viagra, 1998), a drug recently approved for the treatment of male erectile dysfunction.





PDE5 is an enzyme that accepts cGMP and breaks it down. The kinetics of binding 3Hsildenafil and 3Htadalafil to the catalytic site of PDE5.

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Both inhibitors bind with high affinity and specificity, and cGMP binding to the allosteric sites stimulates binding of PDE5 inhibitors at the catalytic site. The kinetics of inhibitor binding and inhibition of catalysis imply the existence of two PDE5 conformers, and results of native gel electrophoresis reveal that PDE5 exists in two apparently distinct conformations, i.e., an extended conformer and a more compact conformer.

PDE5 activity is modulated by a rapidly reversible redox switch. Chemical reduction of PDE5 relieves autoinhibition of enzyme functions; allosteric cGMP-binding activity is increased 10-fold, and catalytic activity is increased ~3-fold. The redox effect on allosteric cGMP-binding occurs in the isolated regulatory domain. A change in the state of reduction of PDE5 or the isolated regulatory domain is associated with an apparent conformational change similar to that caused by phosphorylation.

PDE5 is expressed in human colonic cells and in intestinal tissue and its activity is regulated by intracellular cGMP levels in these cells that increase on GCC activation. This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme.

The mechanism of action of E4021 on both the nonactivated and activated forms of rod PDE6 because both states are relevant to understanding how PDE5-selective inhibitors may alter signal transduction pathways in photoreceptor cells. PDE5-selective inhibitors may show good discrimination of PDE5 from most other PDE isoforms.






Pfizer needed a chemical that would gum up PDE5 and keep it from doing its job. The chemical that Pfizer discovered is called sildenafil citrate. It fits right into the PDE5 enzyme and disables it.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with Viagra on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, Viagra should not cause an erection.

Viagra (Sildenafil) is a member of a family of drugs called PDE5 Inhibitors. Viagra was the first PDE5 inhibitor on the market. FDA approved Viagra on March 27, 1998. http://www.viagra.com/ Viagra?? contains sildenafil citrate packaged as a pill.

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When a man takes a Viagra?? pill, the sildenafil citrate flows throughout his body, but it really only affects the PDE5 enzyme in the penis. The drug stays in the bloodstream for about four hours, and then it is washed out of the blood by the liver and kidneys.

Researchers are investigating a newer version of drugs that inhibit the enzyme targeted by sildenafil, phosphodiesterase-5 (PDE5).






Particular caution should be used when prescribing PDE5 inhibitors for http://www.viagrapunch.com/what_is_ed.html erectile dysfunction for patients receiving protease inhibitors, including Reyataz. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.






PDE5 drugs are very effective. PDE5 drugs appear to work in men regardless of why they have erectile dysfunction ??? including vascular disease, nerve problems and even psychological causes. PDE5 drugs can cause a number of minor side effects, including headache, lightheadedness, dizziness, flushing and change in Visual perception|vision. A few men choose not to use one of these drugs because they are bothered by these side effects.






Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.






There are now three oral ED drugs; Viagra, (sildenafil) by Pfizer; Levitra (vardenafil) by Bayer Pharmaceutical and Glaxo-Smith-Kline-Beecham/ Schering Plough; and Cialis (tadalafil) by LillyICOS.

The dilemma: which drug to choose and why.

For all practical purposes, these drugs including Viagra, Levitra, and Cialis are the first line of oral treatment for males with erectile dysfunction. In certain circumstances in which the males are young, no comorbidities are recognized, and laboratory tests are normal one should look for the etiology of their erectile dysfunction before instituting treatment since the disease process may be more serious than the symptoms, i.e., the ED itself. In some cases, treatment of the primary disease may in fact resolve the sexual dysfunction. However, most men have a cause for their ED as noted by the history and physical examination and the laboratory tests and PDE-5 inhibitors are the first line of choice.

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Viagra
Viagra was the first and is probably the most famous of the three PDE-5 inhibitors used to treat erectile dysfunction. Initially there was concern about cardiovascular deaths, however, with time it is obvious that this drug is extremely safe when used correctly and of the three drugs has been out there the longest with the most medications and the most sexual situations of any of the three.

Levitra
Levitra was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved approximately two years ago. Studies done on Levitra have excluded patients who failed Viagra and therefore the efficacies are somewhat shifted toward the positive. In general, the feeling is that Levitra is more potent and efficient than Viagra as demonstrated by the hard-to-treat groups of patients.

Cialis
Cialis has been approved for duration of 36 hours; however, there are studies showing high efficacy out to 100 hours. It is not affected by any food whatsoever and in fact can be taken with pure fat. Viagra, on the other hand, is impeded by any type of food and Levitra absorption is impeded by a high-fat diet in which more than 62% of the fat and the food energy are from fat.






  • Phosphodiesterase</br>

  • PDE5 inhibitor







  • Bakre MM, Sopory S, Visweswariah SS.Expression and regulation of the cGMP-binding, cGMP-specific phosphodiesterase (PDE5) in human colonic epithelial cells: role in the induction of cellular refractoriness to the heat-stable enterotoxin peptide.J Cell Biochem. 2000 Feb;77(1):159-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=10679826&dopt=abstract PMID: 10679826</br>

  • VIAGRA??, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-http://www.fda.gov/cder/foi/label/1998/viagralabel2.pdf specific phosphodiesterase type 5 (PDE5).







  • http://www.pfizer.com/download/uspi_viagra.pdf Pfizer Pharmaceutical</br>

  • http://www.fda.gov/ FDA Official Website</br>

  • http://www.cpa-apc.org/Publications/Archives/CJP/2004/october/stevenson.asp Review Paper for Sexual Medicine</br>

  • http://www.mercola.com/2002/jul/20/orgasm.htm New Scientist article on Viagra and the female 'G spot'


Category:PDE5 inhibitors
Category:EC 3.1.4


This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "CGMP specific phosphodiesterase type 5".


Last Modified:   2005-12-19


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