Sildenafil

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"Viagra" redirects here. For other uses, see Viagra (disambiguation).
Sildenafil
File:Sildenafil.svg
File:Sildenafil-from-xtal-3D-balls.png
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
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic (mostly CYP3A4, also CYP2C9)
Biological half-life 3 to 4 hours
Excretion Fecal (80%) and renal (around 13%)
Identifiers
CAS Number 139755-83-2
ATC code G04BE03 (WHO)
PubChem CID 5281023
DrugBank DB00203
ChemSpider 56586
Chemical data
Formula C22H30N6O4S
Molar mass base: 474.6 g/mol[[Script error: No such module "String".]]
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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 developed and is being marketed by the pharmaceutical company Pfizer. It acts by inhibiting cGMP specific phosphodiesterase type 5, an enzyme that 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).

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 symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.[1] 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.[2][3] 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.[4] It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.[citation needed]

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes.[5] Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.[citation needed]

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.[6] 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.[7]

In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills.[8] By 2007, Viagra's global share had plunged to about 50 percent[9] 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.[10][11]

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 aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[12]

Pfizer's worldwide patents on sildenafil citrate will expire in 2010–2013.[13] 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.[14][15]

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 the receptors of an enzyme called guanylate cyclase 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.[16] Robert F. Furchgott won the Nobel Prize in Physiology or Medicine in 1998 for his discovery and analysis of endothelium-derived relaxing factor or "EDRF", later identified with NO itself or a closely-related compound.

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.[16] 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.[17]

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.[18]

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.[19] Following up to earlier reports from 1999,[20] the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.[21]

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.[22]

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.[23][24] 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.[25]

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.[26]

Non-medical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[27] 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.[28] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[28] 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, and having sex within a stable relationship. 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.[29] This study also noted a significant placebo effect in the control group.[29]

Unprescribed recreational use of sildenafil and other PDE-5 Inhibitors is noted as particularly high among users of illegal drugs.[30][31] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[28] 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."[28] Mixing with amyl nitrite is particularly dangerous, and is potentially fatal.[28]

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.[32] Their research was published in the Proceedings of the National Academy of Sciences.[33]

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.[34] 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.[35]

The United States FDA has banned numerous products claiming to be Eurycoma longifolia which in fact only contain analogs of sildenafil.[36][37][38] Peddlers of such fake herbals typically respond by just changing the names of their products.

Dosage

File:Viagra in Pack.jpg
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.[39]

Contraindications

Contraindications include:[citation needed]

Side 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.[41] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[42] 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[43] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[44][45][46][47][48][49]

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.[41] 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.[50]

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.[51]

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.[52]

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.[53]

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:[54]

  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.

See also

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Notes

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External links

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Urologicals, including antispasmodics (G04B)
Acidifiers
Urinary antispasmodics
(primarily antimuscarinics)
For erectile dysfunction
Avanafil · Sildenafil · Tadalafil · Udenafil · Vardenafil
Others
Other urologicals
Medications used in the management of pulmonary arterial hypertension (B01, C02)
Prostacyclin analogues
Endothelin receptor antagonists
PDE5 inhibitors
Sildenafil, Tadalafil
Adjunctive therapy
PDE1
PDE2
PDE3
PDE4
PDE5
Acetildenafil • Avanafil • Dipyridamole • Icariin • Lodenafil • Mirodenafil • MY-5445 • Sildenafil • T-0156 • Tadalafil • Thiomethisosildenafil • Udenafil • Vardenafil
PDE6
PDE7
PDE9
PDE10
Nonselective
ar:سيلدينافيل

ca:Sildenafil cs:Sildenafil da:Viagra de:Sildenafil es:Sildenafilo eu:Sildenafilo fa:سیلدنافیل fr:Sildénafil ko:실데나필 id:Sildenafil it:Sildenafil he:ויאגרה hu:Szildenafil arz:سيلدنافيل nl:Sildenafil ja:シルデナフィル no:Sildenafil ps:سيلدينافيل pl:Sildenafil pt:Sildenafila ru:Силденафил sq:Sildenafil scn:Sildenafil simple:Sildenafil sl:Sildenafil fi:Sildenafiili sv:Sildenafil ta:வயாகரா th:ซิลเดนาฟิลซิเตรต tr:Sildenafil uk:Силденафіл vi:Viagra bat-smg:Sildenafil

zh:西地那非
  1. ↑ Aubetawe Bro Morgannwg University NHS Trust (2008-07-04). "Research at ABM". Retrieved 2008-08-06. [dead link]
  2. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ 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. doi:10.1016/0960-894X(96)00323-X. 
  4. ↑ Kling J (1998). "From hypertension to angina to Viagra" (– Scholar search). Mod Drug Discov. 1: 31–38. [dead link][dead link]
  5. ↑ Bellis M. "Viagra, the patenting of an aphrodisiac". About.com. Retrieved 2009-02-10. 
  6. ↑ "Missouri fines internet pharmacy". British Medical Journal. Retrieved 2010-07-07. 
  7. ↑ "Urban Dictionary: Vitamin V". Urban Dictionary. January 16, 2009. Retrieved 2009-02-10. 
  8. ↑ Keith A (2000). "The economics of Viagra" (PDF). Health Aff (Millwood). 19 (2): 147–57. doi:10.1377/hlthaff.19.2.147. PMID 10718028. Retrieved 2009-02-10. 
  9. ↑ McGuire, Stephen (1 January 2007). "Cialis gaining market share worldwide". Medical Marketing & Media. Haymarket Media. Retrieved 2009-02-10. 
  10. ↑ Mullin, Rick (June 20, 2005). "Viagra". Chemical & Engineering News. 83 (25). Retrieved 2008-08-20. 
  11. ↑ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. Retrieved 2008-08-20. 
  12. ↑ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. Retrieved 2009-02-10. 
  13. ↑ Viagra patent expires in June, says Brazilian court
  14. ↑ Murray-, Rosie (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. Retrieved 2009-02-10. 
  15. ↑ "Pfizer Loses UK Battle on Viagra Patent". UroToday. Thomson Reuters. 17 June 2002. Retrieved 2009-02-10. 
  16. ↑ 16.0 16.1 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. 
  17. ↑ "Viagra Clinical Pharmacology". RxList.com. 2008. Retrieved 2008-08-20. 
  18. ↑ Vardi M, Nini A (2007). "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". Cochrane Database Syst Rev (1): CD002187. doi:10.1002/14651858.CD002187.pub3. PMID 17253475. 
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  21. ↑ 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. 
  22. ↑ Pfizer, Inc. (June 6, 2005). "FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension". 2005 News Releases. Pfizer. Retrieved December 27, 2005. [dead link]
  23. ↑ 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. 
  24. ↑ 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. 
  25. ↑ 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.2007.1055. PMID 17584008. 
  26. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  27. ↑ Peterson K (2001-03-21). "Young men add Viagra to their drug arsenal". USAToday. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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  32. ↑ "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. Retrieved 2009-02-10. 
  33. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  34. ↑ Oh SS, Zou P, Low MY, Koh HL. Detection of sildenafil analogues in herbal products for erectile dysfunction (2006). Journal of Toxicology and Environmental Health Part A. 69 (21): 1951–1958. PMID 16982533.  Missing or empty |title= (help)
  35. ↑ Venhuis BJ, Blok-Tip L, de Kaste D (2008). "Designer drugs in herbal aphrodisiacs". Forensic Science International. 177 (2-3): 25–27. PMID 18178354. 
  36. ↑ FDA letter to Libidus distributor
  37. ↑ FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement
  38. ↑ Hidden Risks of Erectile Dysfunction "Treatments" Sold Online
  39. ↑ "Pill Identifier". Drugs.com. 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. 
  40. ↑ 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. 
  41. ↑ 41.0 41.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  42. ↑ "Viagra and vision". VisionWeb. 29 October 2001. Retrieved 2009-02-10. 
  43. ↑ "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. Retrieved 2009-02-10. 
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  49. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  50. ↑ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". United States Food and Drug Administration. 18 October 2007. Retrieved 2009-02-10. 
  51. ↑ "Viagra (sildenafil citrate) tablets" (PDF). page 29: Pzifer. October 2007. Retrieved 2009-10-25. 
  52. ↑ 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. 
  53. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1427-1429.
  54. ↑ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev. 2005 (1): 88–97. doi:10.1021/op040019c. 
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