PDE5 inhibitor

Sildenafil (Viagra), the prototypical PDE5 inhibitor

A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 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 abnormally narrow.

Indications

PDE5 inhibitors are clinically indicated for the treatment of erectile dysfunction. Sildenafil citrate, one of the PDE5 inhibitors, is also indicated for the treatment of pulmonary hypertension. Other PDE5 inhibitors such as tadalafil and vardenafil have been studied as other possible treatments for this disease.

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.^[1]

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.^[2]

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.^[2]

On October 18, 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.^[3]

Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy^[4]

Other ADRs and their incidence vary with the agent and are listed in their individual pages.

Drug interactions

PDE5 inhibitors are primarily metabolised 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, itraconazole, and other anti-hypertensive drugs such as Nitro-spray (due to its capacity to diminish blood pressure).^[2]

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 citrate
• tadalafil
• vardenafil
• udenafil

Note that while these drugs preferentially inhibit PDE5, none of them is 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.

Claimed newer inhibitors are icariin, an active component of Epimedium grandiflorum^{[citation needed]} and possibly 4-Methylpiperazine and Pyrazolo Pyrimidin-7-1, said to be components of the lichen Xanthoparmelia scabrosa.^{[citation needed]}

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 phosphodiesterase type 5 (PDE5), increasing bloodflow to the penis during sexual stimulation.

This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.

Notes

1. ^ Zhang, R. et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33, 2675–80 (2002)
2. ^ ^{a b c} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
3. ^ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109012.htm. Retrieved 2011-10-30. 
4. ^ Amrith R. Rao, Ali Thwaini, Hashim U. Ahmed, Iqbal S. Shergill and Suks Minhas. "THE PHOSPHODIESTERASE INHIBITORS AND NON-ARTERITIC ANTERIOR ISCHAEMIC OPTIC NEUROPATHY: INCREASED VIGILANCE IS NECESSARY". http://www3.interscience.wiley.com/journal/118507859/abstract?CRETRY=1&SRETRY=0. 

References

• Uzunov, P. and Weiss, B.: Separation of multiple molecular forms of cyclic adenosine 3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim. Biophys. Acta 284:220-226, 1972.
• Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.
• Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.
• Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.
• Kanthapillai P, Lasserson TJ, Walters EH. Sildenafil for pulmonary hypertension. Cochrane Database Syst Rev 2004;18(4):CD003562. PMID 15495058
• Amrith R. Rao, Ali Thwaini, Hashim U. Ahmed, Iqbal S. Shergill and Suks Minhas. THE PHOSPHODIESTERASE INHIBITORS AND NON-ARTERITIC ANTERIOR ISCHAEMIC OPTIC NEUROPATHY: INCREASED VIGILANCE IS NECESSARY. British Journal of Urology. 2007 100. 1:3-4