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The Viagra Molecule

Sildenafil

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Viagra -- Sildenafil Citrate

Sildenafil citrate, sold under the names Viagra, Revatio and under various other names, is a drug used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH), developed by the pharmaceutical company Pfizer. Its primary competitors on the market are tadalafil (Cialis), and vardenafil (Levitra).

History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.[1][2] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.[3] It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim which Pfizer disputes.[4] Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience. Even though sildenafil is available by prescription from a doctor, it was advertised directly to consumers on U.S. TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", a mere web questionnaire. The "Viagra" name has become so well known that many fake aphrodisiacs now call themselves "herbal Viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", as well as various other nicknames.

In February 2007, it was announced that Boots the Chemist would trial over the counter sales of Viagra in stores in Manchester, England. Men aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[5] Pfizer's worldwide patents on sildenafil citrate will expire in 2011–2013. The UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

Mechanism of action

Part of the physiological process of erection involves the parasympathetic nervous system causing the release of nitric oxide (NO) in the corpus cavernosum of the penis. NO binds to the receptors of the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) in the corpus cavernosum, resulting in increased inflow of blood and an erection.

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. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis®) and vardenafil (Levitra®). Sildenafil is metabolised by hepatic enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, there may be a delay in absorption of sildenafil and the peak effect might be reduced slightly as the plasma concentration will be lowered.

Contraindications

Contraindications include: When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")[6]

In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors

Severe hepatic impairment (decreased liver function) Severe impairment in renal function

Hypotension (low blood pressure) Recent stroke or heart attack

Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

Side effects

Amongst sildenafil's rare but serious adverse effects are: priapism, severe hypotension, myocardial infarction, ventricular arrhythmias, stroke and increased intraocular pressure.[citation needed] Common side effects include sneezing, headache, flushing, dyspepsia, palpitations and photophobia.

Care should be exercised by patients who are also taking Protease inhibitors for the treatment of HIV. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side-effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25-mg dose every 48 hours.[citation needed]

Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). [7]. Some complained of blurriness and loss of peripheral vision. In May of 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment[8] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[9][10][11][12][13][14]

In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors.[15] When used with an alpha blocker, hypotension (low blood pressure) may occur, but this effect does not occur if they are taken at least four hours apart.[16]

Other uses

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This in turn reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.[17]

Raynaud's phenomenon

In 2005, Dr. Roland Fries and colleagues reported that sildenafil cut the frequency of Raynaud's phenomenon attacks, reduced their duration by roughly one half, and more than quadrupled the mean capillary blood velocity. This was a double-blind, placebo-controlled crossover trial and the patients had both the primary and secondary forms and had all discontinued the more conventional treatments for this.[18]

Altitude sickness

Sildenafil has been shown to be useful for the prevention and treatment of High altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers.[19][20] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, particularly in situations where the standard treatment of rapid descent has been delayed for some reason.[21]

Notes

  1. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int J Impot Res 8 (2): 47–52. PMID 8858389. 
  2. Terrett NK et al (1996). "Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction". Bioorg Med Chem Lett 6: 1819–1824. 
  3. Kling J (1998). "From hypertension to angina to Viagra". Mod Drug Discov 1: 31–38. 
  4. Bellis M. Viagra, the patenting of an aphrodisiac. About.com.
  5. Over-the-counter Viagra piloted. British Broadcasting Corporation (2007-02-11).
  6. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM (1999). "ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association". Journal of the American College of Cardiology 33 (1): 273-82. PMID 9935041. 
  7. Viagra and vision. visionweb (n.d.).
  8. Alert for Healthcare Professionals: Sildenafil citrate (marketed as Viagra). United States Food and Drug Administration (July 2005).
  9. Pomeranz HD and Bhavsar AR (2005). "Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases". J Neuroophthalmol 25 (1): 9-13. 
  10. Egan R and Pomeranz H (2000). "Sildenafil (Viagra) associated anterior ischemic optic neuropathy". Arch Ophthalmol 118 (2): 291-2. 
  11. Pomeranz HD, Smith KH, Hart WM, Egan RA (2002). "Sildenafil-associated nonarteritic anterior ischemic optic neuropathy". Ophthalmology 109 (3): 584-7. 
  12. Cunningham AV and Smith KH (2001). "Anterior ischemic optic neuropathy associated with viagra". J Neuroophthalmol 21 (1): 22-5. 
  13. Boshier A, Pambakian N, Shakir SA (2002). "A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil". Int J Clin Pharmacol Ther 40 (9): 422-3. 
  14. Akash R, Hrishikesh D, Amith P, Sabah S (2005). "Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra". J Ocul Pharmacol Ther 24 (4): 315-7. 
  15. FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. Food and Drug Administration (2007-10-18). Retrieved on 2007-12-08.
  16. Kloner RA (2005). "Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions". Am J Cardiol 96 (12B): 42M-46M. 
  17. Pfizer, Inc. (June 6, 2005). FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension. 2005 News Releases. Pfizer. Retrieved on December 27, 2005.
  18. Fries, Roland; Kaveh Shariat, Hubertus von Wilmowsky, and Michael Böhm (November 8, 2005). "Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy". Circulation 112 (19): 2980-5. PMID 16275885. 
  19. Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, Cornolo J. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine. 2005 Feb 1;171(3):275-81.
  20. Perimenis P. Sildenafil for the treatment of altitude-induced hypoxaemia. Expert Opinion on Pharmacotherapy. 2005 May;6(5):835-7.
  21. Fagenholz PJ, Gutman JA, Murray AF, Harris NS. Treatment of high altitude pulmonary edema at 4240 m in Nepal. High Altitude Medicine and Biology. 2007 Summer;8(2):139-46.
  22. Peterson K. "Young men add Viagra to their drug arsenal", USAToday, 2001-03-21. 
  23. Siegel-Itzkovich J (1999). "Viagra makes flowers stand up straight". Student BMJ (9). 
  24. [1]
  25. Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek. Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules. PNAS 2007, 104, 9834–9839. doi:10.1073/pnas.0703388104
  26. Dunn PJ. "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev 2005 (1): 88-97. doi:S1083-6160(04)00019-2 10.1021/op040019c S1083-6160(04)00019-2. 

 

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