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| {{CMG}}
| | #REDIRECT [[Sildenafil#Structure]] |
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| ==[[Sildenafil (patient information)|For patient information, click here]]==
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| ==Overview==
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| '''Sildenafil citrate''', sold under the names '''Viagra''', '''Revatio''' and under various other names, is a [[Medication|drug]] used to treat male [[erectile dysfunction]] (impotence) and [[pulmonary hypertension|pulmonary arterial hypertension]] (PAH), developed by the [[pharmaceutical company]] [[Pfizer]]. Its primary competitors on the market are [[tadalafil]] (Cialis), and [[vardenafil]] (Levitra).
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| ==History==
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| 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 trial]]s under the direction of [[Ian Osterloh]] suggested that the drug had little effect on angina, but that it could induce marked penile [[erection]]s.<ref>{{cite journal | author=Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C | title=Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction | journal=Int J Impot Res | year=1996 | pages=47–52 | volume=8 | issue=2 | id=PMID 8858389}}</ref><ref>{{cite journal|author=Terrett NK ''et al''|title=Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction|journal=Bioorg Med Chem Lett|year=1996|volume=6|pages=1819–1824}}<!--not indexed on Medline--></ref> 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.<ref>{{cite journal|author=Kling J|title=From hypertension to angina to Viagra|journal=Mod Drug Discov|year=1998|volume=1|pages=31–38|url=http://pubs.acs.org/hotartcl/mdd/98/novdec/viagra.html}}<!--Not indexed on PubMed--></ref> It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
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| The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim which Pfizer disputes.<ref name=bellis>{{cite web|author=Bellis M|url=http://inventors.about.com/library/weekly/aa013099.htm|title=Viagra, the patenting of an aphrodisiac|publisher=About.com}}</ref> Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.
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| Even though sildenafil is available by prescription from a doctor, it was advertised directly to consumers on US 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.
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| In February 2007, it was announced that [[Boots the Chemist]] would trial [[Over-the-counter drug|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]].<ref>{{cite web|url=http://news.bbc.co.uk/1/hi/health/6351171.stm|title=Over-the-counter Viagra piloted|publisher=British Broadcasting Corporation}}</ref>
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| Pfizer's worldwide patents on sildenafil citrate will expire in 2011–2013. The UK patent held by Pfizer on the use of [[PDE5 inhibitor]]s (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.
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| ==Mechanism of action==
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| Part of the physiological process of erection involves the [[parasympathetic nervous system]] causing the release of [[nitric oxide]] (NO) in the [[corpus cavernosum penis|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.
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| 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 penis|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®).
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| Sildenafil is [[metabolism|metabolised]] by [[liver|hepatic]] [[enzyme]]s and excreted by both the [[liver]] and [[kidney]]s. 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.
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| ==Dosage and price==
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| As with all [[prescription drug]]s, proper dosage is at the discretion of a licensed medical [[Physician|doctor]]. The dose of sildenafil is 25 mg to 100 mg taken once per day between 30 minutes and 4 hours prior to [[sexual intercourse]].
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| It is usually recommended to start with a dosage of 50 mg and then lower or raise the dosage as appropriate. The drug is sold in three dosages (25, 50, and 100 mg), all three costing about US$10 per pill. Name-brand Viagra sildenafil is not scored and a fairly hard coating makes it more difficult to accurately cut the pills in half, even with a pill cutter.
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| Viagra pills are blue and diamond-shaped with the words "Pfizer" on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) on the other.
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| ==Contraindications==
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| [[Contraindications]] include:
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| * When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), [[sodium nitroprusside]], [[amyl nitrite]] ("[[poppers]]")<ref>{{cite journal | author=Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM | title=ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association | journal=Journal of the American College of Cardiology | year=1999 | pages=273-82 | volume=33 | issue=1 | id=PMID 9935041 | url=http://www.acc.org/clinical/consensus/viagra.htm }}</ref>
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| * In men for whom [[sexual intercourse]] is inadvisable due to [[cardiovascular]] risk factors
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| * Severe hepatic impairment (decreased liver function)
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| * Severe impairment in [[renal function]]
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| * [[Hypotension]] (low blood pressure)
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| * Recent [[stroke]] or [[myocardial infarction|heart attack]]
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| * Hereditary degenerative [[retinal disorders]] (including genetic disorders of retinal [[phosphodiesterase]]s)
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| ==Side effects==
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| Amongst sildenafil's rare but serious adverse effects are: [[priapism]], severe [[hypotension]], [[myocardial infarction]], [[ventricular arrhythmia]]s, [[stroke]] and increased [[intraocular pressure]].
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| Common side effects include [[Sneeze|sneezing]], [[headache]], [[Flushing (physiology)|flushing]], [[dyspepsia]], prolonged erections, [[palpitation]]s and [[photophobia]]. Visual changes including blurring of vision and a curious bluish tinge have also been reported.
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| Care should be exercised by patients who are also taking [[Protease inhibitor (pharmacology)|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.
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| Some sildenafil users have 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<ref>{{cite web|url=http://www.fda.gov/cder/drug/InfoSheets/HCP/sildenafilHCP.htm|title=Alert for Healthcare Professionals: Sildenafil citrate (marketed as Viagra)|date=July 2005|publisher=United States Food and Drug Administration}}</ref> and a number of studies have linked sildenafil use with [[Anterior ischemic optic neuropathy|nonarteritic anterior ischemic optic neuropathy]].<ref>{{cite journal|author=Pomeranz HD and Bhavsar AR|title=Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases|journal=J Neuroophthalmol|year=2005|volume=25|issue=1|pages=9-13|PMID 15756125}}</ref><ref>{{cite journal|author=Egan R and Pomeranz H|title=Sildenafil (Viagra) associated anterior ischemic optic neuropathy|journal=Arch Ophthalmol|year=2000|volume=118|issue=2|pages=291-2|PMID 10676804}}</ref><ref>{{cite journal|author=Pomeranz HD, Smith KH, Hart WM, Egan RA|title=Sildenafil-associated nonarteritic anterior ischemic optic neuropathy|journal=Ophthalmology|year=2002|volume=109|issue=3|pages=584-7|PMID 11874765}}</ref><ref>{{cite journal|author=Cunningham AV and Smith KH|title=Anterior ischemic optic neuropathy associated with viagra|journal=J Neuroophthalmol|year=2001|volume=21|issue=1|pages=22-5|PMID 11315976}}</ref><ref>{{cite journal|author=Boshier A, Pambakian N, Shakir SA|title=A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil|journal=Int J Clin Pharmacol Ther|year=2002|volume=40|issue=9|pages=422-3|PMID 12358159}}</ref><ref>{{cite journal|author=Akash R, Hrishikesh D, Amith P, Sabah S|title=Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra|journal=J Ocul Pharmacol Ther|year=2005|volume=24|issue=4|pages=315-7|PMID 16117695}}</ref>
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| When used with an [[alpha blocker]], take them at least four hours apart to avoid [[hypotension]].<ref>{{cite journal|author=Kloner RA|title=Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions|journal=Am J Cardiol|year=2005|volume=96|issue=12B|pages=42M-46M|PMID 16387566}}</ref>
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| ==Other uses==
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| ===Pulmonary hypertension===
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| As well as erectile dysfunction, sildenafil citrate is also effective in the [[rare disease]] [[pulmonary hypertension|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 (heart)|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.<ref>{{cite web | author = Pfizer, Inc. | year = June 6, 2005 | url = http://www.pfizer.com/pfizer/are/news_releases/2005pr/mn_2005_0606.jsp | title = FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension | work = 2005 News Releases | publisher = Pfizer}}</ref>
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| ===Raynaud's phenomenon===
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| 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.<ref>{{cite journal | first = Roland | last = Fries | coauthors = Kaveh Shariat, Hubertus von Wilmowsky, and Michael Böhm | date = November 8, 2005 | title = Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy | journal = Circulation | volume = 112 | issue = 19 | pages = 2980-5 | id = PMID 16275885 | url = http://circ.ahajournals.org/cgi/content/full/112/19/2980 }}</ref>
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| ==Non-medical use==
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| ===Aphrodisiac===
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| Sildenafil is commonly and increasingly used as an [[aphrodisiac]]. While there is no clinical evidence that it has aphrodisiac activity, many seem to believe it will improve sexual performance as well as erectile function and enhance the sexual experience that will occur.{{Fact|date=February 2007}}
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| ===Recreational use===
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| Viagra's popularity with young adults has increased over the years.<ref>{{cite news|author=Peterson K|url=http://www.usatoday.com/news/health/2001-03-21-viagra-abuse.htm|title=Young men add Viagra to their drug arsenal|publisher=USAToday|date=2001-03-21}}</ref> It is sometimes used recreationally. Some users mix Viagra with [[methylenedioxymethamphetamine]] (MDMA, ecstasy) in an attempt to compensate for the side effect common to many amphetamines of erectile dysfunction, a combination known as "[[sextasy]]", "rockin' and rollin'", or 'trail mix'."
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| ===Prevention of plant wilting===
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| A low-concentration solution of sildenafil in water significantly prolongs the time before cut flowers wilt; one experiment showed a doubling in time from one week to two weeks. The mechanism of action is similar to that in humans: nitric oxide leads to the production of cGMP whose degradation by PDE5 is inhibited by sildenafil.<ref>{{cite journal|author=Siegel-Itzkovich J|url=http://www.studentbmj.com/issues/99/09/news/313.php|title=Viagra makes flowers stand up straight|journal=Student BMJ|year=1999|issue=9}}</ref>
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| ==Chemical synthesis==
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| The preparation steps for synthesis of Viagra (sildenafil citrate) are as follows:
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| # [[Methylation]] of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate.
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| # [[Hydrolysis]] with aqueous NaOH to free acid.
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| # [[Nitration]] with oleum/fuming nitric acid.
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| # Carboxamide formation with refluxing thionyl chloride/NH4OH.
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| # [[Redox|Reduction]] of nitro group to amino.
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| # [[Acylation]] with 2-ethoxybenzoyl chloride. | |
| # Cyclization.
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| # [[Sulfonation]] to the chlorosulfonyl derivative.
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| # [[Condensation]] with 1-methylpiperazine.<ref>{{cite journal|journal = Org Process Res Dev|volume = 9 |issue =1 |pages = 88-97| volume = 2005 |doi = 10.1021/op040019c S1083-6160(04)00019-2| title = Synthesis of Commercial Phosphodiesterase(V) Inhibitors | author = Dunn PJ }}</ref>
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| ==See also==
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| * [[Tadalafil]] (Cialis)
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| * [[Vardenafil]] (Levitra)
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| * [[Yohimbine]]
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| ==Notes==
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| <div class="references-small">
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| <references/>
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| </div>
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| ==External links==
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| * [http://www.viagra.com/ Home page for Viagra]
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| * [http://www.pfizer.com/ Pfizer Pharmaceutical (Company website)] - manufacturer of Viagra; [http://www.pfizer.com/download/uspi_viagra.pdf prescribing information] available in PDF format.
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| * [http://www.fda.gov/cder/consumerinfo/viagra/ FDA Web Site for Viagra Consumer Information]
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| *[http://www.fda.gov/cder/foi/label/2005/020895s021lbl.pdf FDA current Viagra label (a form of clinical information and report)]
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| *[http://www.nlm.nih.gov/medlineplus/print/druginfo/uspdi/203533.html MedlinePLUS drug Information] - Side Effects of sildenafil
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| * [http://science.howstuffworks.com/viagra.htm/printable How Viagra Works] - Howstuffworks article
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| * [http://www.myscienceproject.org/viagra-flowers.html Does Viagra Keep Flowers From Wilting?]
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| {{Urologicals}}
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