Sildenafil

"Viagra" redirects here. For other uses, see Viagra (disambiguation).

Sildenafil

Systematic (IUPAC) name
1-[4-ethoxy-3-(6,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine
Clinical data
Trade names	Viagra
AHFS/Drugs.com	monograph
MedlinePlus	a699015
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B(US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	40%
Metabolism	Hepatic (mostly CYP3A4, also CYP2C9)
Half-life	3 to 4 hours
Excretion	Fecal (80%) and renal (around 13%)
Identifiers
CAS number	139755-83-2 Y
ATC code	G04BE03
PubChem	CID 5281023
DrugBank	DB00203
ChemSpider	56586 Y
UNII	3M7OB98Y7H Y
KEGG	D08514 Y
ChEBI	CHEBI:58987 Y
ChEMBL	CHEMBL1737 N
Chemical data
Formula	C22H30N6O4S
Mol. mass	base: 474.6 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C22H30N6O4S.C6H8O7/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28;7-3(8)1-6(13,5(11)12)2-4(9)10/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12) Y Key:DEIYFTQMQPDXOT-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer.^[1] It acts by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme that delays degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).

Medical uses

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.^[2]

People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation.^[3] Following up to earlier reports from 1999,^[4] the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.^[5]

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.^[6]

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.^[7][8] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.^[9]

Dosage

Viagra

Viagra pills are blue and diamond-shaped with the word "Pfizer" engraved on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) engraved on the other. The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse.

The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.^[10]

Adverse effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision.^[11] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).^[12] Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment in rare cases^[13] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.^{[14][15][16][17][18][19]}

Rare but serious adverse effects found through postmarketing surveillance include priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.^[11] As a result of these postmarketing reports, in October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.^[20]

Interactions

Care should be exercised by patients that 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.^[21]

Concomitant use of sildenafil and an alpha blocker may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.^[22]

Contraindications

Contraindications include:^{[citation needed]}

• When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")^[23]
• 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)

Non-medical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.^[24] Sildenafil's trade name "Viagra" is widely recognized in popular culture, and the drug's association with treating erectile dysfunction has led to its recreational use.^[25] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,^[25] or permanently increases penis size^{[citation needed]}. Studies on the effects of viagra when used recreationally are limited, but suggest that it has little effect when used by those not suffering from erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the post-ejaculatory refractory time.^[26] This study also noted a significant placebo effect in the control group.^[26]

Unprescribed recreational use of sildenafil and other PDE-5 Inhibitors is noted as particularly high among users of illegal drugs.^[27][28] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.^[25] Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as "sextasy", "rockin' and rollin'," or "trail mix."^[25] Mixing with amyl nitrite is particularly dangerous and potentially fatal.^[25]

Jet lag research

The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina for their discovery that Viagra aids jet lag recovery in hamsters.^[29] Their research was published in the Proceedings of the National Academy of Sciences.^[30]

Use in sports

Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe that it will enhance their performance.^[31]

Analogs

Acetildenafil is a structural analog of sildenafil, one of the PDE₅ inhibitors found in a number of "herbal" aphrodisiac products sold over-the-counter. This class of analogs has not undergone any of the rigorous testing that drugs like sildenafil have passed, and, thus, has an unknown side-effect profile.^[32] Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.^[33]

The United States FDA has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil.^[34][35][36] Peddlers of such fake herbals typically respond by just changing the names of their products.

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantitated in plasma, serum or whole blood in order to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.^[37]

Mechanism of action

The mechanism of action of sildenafil involves the protection of cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection.^[38] Robert F. Furchgott, Ferid Murad and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.

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.^[38] 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 liver enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.^[39]

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:^[40]

1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
2. Hydrolysis with aqueous NaOH to free acid
3. Nitration with oleum/fuming nitric acid
4. Carboxamide formation with refluxing thionyl chloride/NH₄OH
5. Reduction of nitro group to amino
6. Acylation with 2-ethoxybenzoyl chloride
7. Cyclization
8. Sulfonation to the chlorosulfonyl derivative
9. Condensation with 1-methylpiperazine.

History

Origins

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 symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.^[41] 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][42] 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 US Food and Drug Administration on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.^[43] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.^[44]

The British Press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes.^[45] Their names are on the manufacturing patent application, but the original patent on the synthesis of the the drug was filed by Nicholas Terrett and Peter Ellis.

Marketing and sales

Even though sildenafil is available only 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 soccer star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire.^[46] 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", "Blue Diamond" as well as various other nicknames.^[47]

In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills.^[48] By 2007, Viagra's global share had plunged to about 50 percent^[49] due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors.^[50][51]

In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.^[52]

Patent issues and expirations

A 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.^[53][54] But there are two other patents covering the methods for manufacturing Viagra, and Pfizer has maintained its monopoly on the drug in the UK.^[55]

Pfizer's patent on sildenafil citrate expired in Brazil in 2010^[56]. It was originally believed that Pfizer's patents would expire in the United States in March 2012.^[55][57], but an August 2011 federal district court case raises the prospect that at least one of Pfizer's patents will be valid until 2019.^[58]

References

1. ^ ^{a b} Boolell; 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. ^ Vardi M, Nini A (2007). Vardi, Moshe. ed. "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". Cochrane Database Syst Rev (1): CD002187. doi:10.1002/14651858.CD002187.pub3. PMID 17253475. 
3. ^ Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S (January 2003). "Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial". JAMA 289 (1): 56–64. doi:10.1001/jama.289.1.56. PMID 12503977. http://jama.ama-assn.org/cgi/content/full/289/1/56. 
4. ^ Nurnberg HG, Hensley PL, Lauriello J, Parker LM, Keith SJ (August 1999). "Sildenafil for women patients with antidepressant-induced sexual dysfunction". Psychiatr Serv 50 (8): 1076–8. PMID 10445658. http://psychservices.psychiatryonline.org/cgi/content/full/50/8/1076. 
5. ^ Nurnberg HG, Hensley PL, Heiman JR, Croft HA, Debattista C, Paine S (2008). "Sildenafil Treatment of Women With Antidepressant-Associated Sexual Dysfunction". JAMA 300 (4): 395–404. doi:10.1001/jama.300.4.395. PMID 18647982. 
6. ^ Pfizer, Inc. (June 6, 2005). "FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension". 2005 News Releases. Pfizer. http://www.pfizer.com/pfizer/are/news_releases/2005pr/mn_2005_0606.jsp. Retrieved December 27, 2005. ^{[dead link]}
7. ^ Richalet JP, Gratadour P, Robach P, et al. (2005). "Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension". Am. J. Respir. Crit. Care Med. 171 (3): 275–81. doi:10.1164/rccm.200406-804OC. PMID 15516532. 
8. ^ Perimenis P (2005). "Sildenafil for the treatment of altitude-induced hypoxaemia". Expert Opin Pharmacother 6 (5): 835–7. doi:10.1517/14656566.6.5.835. PMID 15934909. 
9. ^ Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt. Med. Biol. 8 (2): 139–46. doi:10.1089/ham.2007.3055. PMID 17584008. 
10. ^ "Pill Identifier". Drugs.com. http://www.drugs.com/pill_identification.html. Retrieved 2009-02-10. "This site is intended for viewing by the USA audience only. If you are in another country, local laws may not permit access to the medical information contained in this site." 
11. ^ ^{a b} "Viagra Prescribing Information" (PDF). Pfizer. October 2007. http://www.pfizer.com/files/products/uspi_viagra.pdf. Retrieved 2008-08-21. 
12. ^ "Viagra and vision". VisionWeb. 29 October 2001. http://www.visionweb.com/content/consumers/dev_consumerarticles.jsp?RID=85. Retrieved 2009-02-10. 
13. ^ "FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems". United States Food and Drug Administration. 8 July 2005. Archived from the original on February 23, 2008. http://web.archive.org/web/20080223130828/http://www.fda.gov/bbs/topics/NEWS/2005/NEW01201.html. Retrieved 2009-02-10. 
14. ^ Pomeranz; 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. doi:10.1097/00041327-200503000-00003. PMID 15756125. 
15. ^ Egan; Egan R and Pomeranz H (2000). "Sildenafil (Viagra) associated anterior ischemic optic neuropathy". Arch Ophthalmol 118 (2): 291–2. PMID 10676804. 
16. ^ Pomeranz, H; Pomeranz HD, Smith KH, Hart WM, Egan RA (2002). "Sildenafil-associated nonarteritic anterior ischemic optic neuropathy". Ophthalmology 109 (3): 584–7. doi:10.1016/S0161-6420(01)00976-9. PMID 11874765. 
17. ^ Cunningham; Cunningham AV and Smith KH (2001). "Anterior ischemic optic neuropathy associated with viagra". J Neuroophthalmol 21 (1): 22–5. doi:10.1097/00041327-200103000-00006. PMID 11315976. 
18. ^ Boshier; 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. PMID 12358159. 
19. ^ Akash, Raj; 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. doi:10.1089/jop.2005.21.315. PMID 16117695. 
20. ^ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". United States Food and Drug Administration. 18 October 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01730.html. Retrieved 2009-02-10. 
21. ^ "Viagra (sildenafil citrate) tablets". page 29: Pzifer. October 2007. http://www.pfizer.com/files/products/uspi_viagra.pdf. Retrieved 2009-10-25. 
22. ^ 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. doi:10.1016/j.amjcard.2005.07.011. PMID 16387566. 
23. ^ 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. doi:10.1016/S0735-1097(98)00656-1. PMID 9935041. 
24. ^ Peterson K (2001-03-21). "Young men add Viagra to their drug arsenal". USAToday. http://www.usatoday.com/news/health/2001-03-21-viagra-abuse.htm. 
25. ^ ^{a b c d e} Smith, K; F Romanelli (2005). "Recreational use and misuse of phosphodiesterase 5 inhibitors". Journal of the American Pharmacists Association 45 (1): 63–75. doi:10.1331/1544345052843165. 
26. ^ ^{a b} Mondaini, N; R Ponchietti, G H Muir, F Montorsi, F Di Loro, G Lombardi and M Rizzo (2003). "Sildenafil does not improve sexual function in men without erectile dysfunction but does reduce the postorgasmic refractory time". International Journal of Impotence Research 15 (3): 225–228. doi:10.1038/sj.ijir.3901005. PMID 12904810. http://www.nature.com/ijir/journal/v15/n3/abs/3901005a.html. Retrieved 2009-06-12. 
27. ^ McCambridge, J; Mitcheson, L., Hunt, N., Winstock, A. (2006). "The rise of Viagra among British illicit drug users: 5-year survey data". Drug and Alcohol Review 25 (2): 111–113. doi:10.1080/09595230500537167. PMID 16627299. 
28. ^ Eloi-Stiven, M; Channaveeraiah, N.a , Christos, P.J.c , Finkel, M.c , Reddy, R. (November 2007). "Does marijuana use play a role in the recreational use of sildenafil?". Journal of Family Practice 56 (11): 932. 
29. ^ "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. http://www.improbable.com/ig/ig-pastwinners.html#ig2007. Retrieved 2009-02-10. 
30. ^ Agostino, P. V.; Agostino PV, Plano SA, Golombek DA (2007). "Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules". Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9834–9. Bibcode 2007PNAS..104.9834A. doi:10.1073/pnas.0703388104. PMC 1887561. PMID 17519328. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1887561. 
31. ^ "Source: Roger Clemens, host of athletes pop Viagra to help onfield performance". Daily News (Daily News). 10 June 2008. http://www.nydailynews.com/sports/baseball/yankees/2008/06/09/2008-06-09_source_roger_clemens_host_of_athletes_po.html. Retrieved 2009-02-10. 
32. ^ Oh SS, Zou P, Low MY, Koh HL. Detection of sildenafil analogues in herbal products for erectile dysfunction (2006). "Detection of sildenafil analogues in herbal products for erectile dysfunction". Journal of Toxicology and Environmental Health Part A 69 (21): 1951–1958. doi:10.1080/15287390600751355. PMID 16982533. 
33. ^ Venhuis BJ, Blok-Tip L, de Kaste D (2008). "Designer drugs in herbal aphrodisiacs". Forensic Science International 177 (2–3): 25–27. doi:10.1016/j.forsciint.2007.11.007. PMID 18178354. 
34. ^ FDA letter to Libidus distributor
35. ^ FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement
36. ^ Hidden Risks of Erectile Dysfunction "Treatments" Sold Online
37. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–1553. http://www.biomedicalpublications.com/dt9.pdf
38. ^ ^{a b} Webb, D.J.; Freestone, S.; Allen, M.J.; Muirhead, G.J. (March 4, 1999). "Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist". Am. J. Cardiol. 83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2. PMID 10078539. 
39. ^ "Viagra Clinical Pharmacology". RxList.com. 2008. http://www.rxlist.com/cgi/generic/viagra_cp.htm. Retrieved 2008-08-20. 
40. ^ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev 2005 (1): 88–97. doi:10.1021/op040019c. 
41. ^ Aubetawe Bro Morgannwg University NHS Trust (2008-07-04). "Research at ABM". http://www.abm.university-trust.wales.nhs.uk/page.cfm?orgId=743&pid=29457. Retrieved 2008-08-06. ^{[dead link]}
42. ^ 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 (15): 1819–1824. doi:10.1016/0960-894X(96)00323-X. 
43. ^ Kling J (1998). "From hypertension to angina to Viagra" (^{Scholar search}). Mod Drug Discov 1: 31–38. http://pubs.acs.org/hotartcl/mdd/98/novdec/viagra.html. ^{[dead link][dead link]}
44. ^ Viagra sales peak at $1,934m in 2008
45. ^ Bellis M. "Viagra, the patenting of an aphrodisiac". About.com. http://inventors.about.com/library/weekly/aa013099.htm. Retrieved 2009-02-10. 
46. ^ Missouri fines internet pharmacy. 319. British Medical Journal. 1999. PMC 1174637. PMID 0. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1174637. 
47. ^ "Urban Dictionary: Vitamin V". Urban Dictionary. January 16, 2009. http://www.urbandictionary.com/define.php?term=Vitamin+V. Retrieved 2009-02-10. 
48. ^ Keith A (2000). "The economics of Viagra" (PDF). Health Aff (Millwood) 19 (2): 147–57. doi:10.1377/hlthaff.19.2.147. PMID 10718028. http://content.healthaffairs.org/cgi/reprint/19/2/147. Retrieved 2009-02-10. 
49. ^ McGuire, Stephen (1 January 2007). "Cialis gaining market share worldwide". Medical Marketing & Media. Haymarket Media. http://www.allbusiness.com/marketing-advertising/marketing-advertising-measures/10557040-1.html. Retrieved 2009-02-10. 
50. ^ Mullin, Rick (June 20, 2005). "Viagra". Chemical & Engineering News 83 (25). http://pubs.acs.org/cen/coverstory/83/8325/8325viagra.html. Retrieved 2008-08-20. 
51. ^ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. http://www.nytimes.com/2005/12/04/business/yourmoney/04impotence.html. Retrieved 2008-08-20. 
52. ^ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. http://news.bbc.co.uk/1/hi/health/6351171.stm. Retrieved 2009-02-10. 
53. ^ Murray-, Rosie (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. http://www.telegraph.co.uk/money/main.jhtml?xml=/money/2002/01/24/cnviag24.xml. Retrieved 2009-02-10. 
54. ^ "Pfizer Loses UK Battle on Viagra Patent". UroToday. Thomson Reuters. 17 June 2002. http://www.urotoday.com/browse_categories/erectile_dysfunction/pfizer_loses_uk_battle_on_viagra_patent.html. Retrieved 2009-02-10. 
55. ^ ^{a b} Jim Edwards (October 21, 2009). "What Will Happen When Viagra Goes Generic?". AccessRx.com. http://www.accessrx.com/research/viagra-patent-expires. Retrieved 2011-03-25. 
56. ^ Viagra patent expires in June, says Brazilian court
57. ^ "Patent storm gathering strength". EP Vantage. January 28, 2011. http://www.evaluatepharma.com/Universal/View.aspx?type=Search&query=annus%20horribilis#&&_ViewArgs={%22_EntityType%22%3a0%2c%22_Parameters%22%3a{%22_ContextData%22%3a%22{\%22isEPVantage\%22%3atrue%2c\%22percentage\%22%3a-1%2c\%22searchWords\%22%3a\%22\%22%2c\%22sectionID\%22%3a\%22\%22%2c\%22storyID\%22%3a235841%2c\%22notSub\%22%3afalse}%22}%2c%22_Type%22%3a1}. Retrieved 2011-02-18. 
58. ^ "Pfizer Defends Viagra from Generic Challenge in Patent Fight with Teva". Corporate Counsel. August 17, 2011. http://www.law.com/jsp/cc/PubArticleFriendlyCC.jsp?id=1202511324824. Retrieved 2011-10-23. 

External links

• Official Viagra Website
• Official Viagra UK Website
• Official Revatio Website
• prescribing information for Viagra and prescribing information for Revatio from Pfizer
• FDA Information
• MedlinePLUS information, including side effects
• U.S. National Library of Medicine: Drug Information Portal - Sildenafil