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Wikipedia

Sildenafil

February 16, 2024

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

Sildenafil, sold under the brand name Viagra, among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.[4][8] It is also sometimes used off-label for the treatment of certain symptoms in secondary Raynaud's phenomenon.[9] It is unclear if it is effective for treating sexual dysfunction in females.[8] It can be taken orally (swallowed by mouth), intravenously (injection into a vein), or through the sublingual route (dissolved under the tongue).[8][10] Onset when taken orally is typically within twenty minutes and lasts for about two hours.[8]

Sildenafil
Clinical data
Pronunciation/sɪlˈdɛnəfɪl/ sil-DEN-ə-fil
Trade namesViagra, Revatio, others
AHFS/Drugs.comMonograph
MedlinePlusa699015
License data
Pregnancy
category
Routes of
administration		Oral (tablets), intravenous, sublingual
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability41% (mean)[7]
Protein binding~96%
MetabolismLiver: CYP3A4 (major route), CYP2C9 (minor route)
MetabolitesN-desmethylsildenafil (~50% potency for PDE5)
Onset of action20 minutes
Elimination half-life3–4 hours
ExcretionFeces (~80%), urine (~13%)[4]
Identifiers
  • 5-{2-Ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-1-methyl-3-propyl-1,6-dihydro-6H-pyrazolo[4,3-d]pyrimidin-7-one
CAS Number
  • 139755-83-2 Y
  • citrate: 171599-83-0 Y
PubChem CID
  • 135398744
  • citrate: 135413523
DrugBank
  • DB00203 Y
  • citrate: DBSALT000347 Y
ChemSpider
  • 5023 Y
  • citrate: 56586 Y
UNII
  • 3M7OB98Y7H
  • citrate: BW9B0ZE037 Y
KEGG
  • D08514 Y
  • citrate: D02229 Y
ChEBI
  • CHEBI:9139 Y
  • citrate: CHEBI:58987 Y
ChEMBL
  • ChEMBL192 Y
  • citrate: ChEMBL1737 Y
PDB ligand
  • VIA (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID6023579
ECHA InfoCard100.122.676
Chemical and physical data
FormulaC22H30N6O4S
Molar mass474.58 g·mol−1
3D model (JSmol)
  • Interactive image
  • CCCC1=NN(C2=C1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)C)OCC)C
  • InChI=1S/C22H30N6O4S/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/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29) N
  • Key:BNRNXUUZRGQAQC-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

Common side effects include headaches, heartburn, and flushed skin.[8] Caution is advised in those with cardiovascular disease.[8] Rare but serious side effects include vision problems, hearing loss, and prolonged erection (priapism) that can lead to damage to the penis.[8] Sildenafil should not be taken by people on nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure.[8] Sildenafil should not be taken within four hours of taking an alpha blocker.

Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis.[8] It requires sexual arousal to work, and does not by itself cause or increase sexual arousal.[8] It also results in dilation of the blood vessels in the lungs.[8]

Pfizer originally discovered the medication in 1989 while looking for a treatment for angina.[11] It was approved for medical use in the United States and in the European Union in 1998.[5][8][11][12] In 2020, it was the 183rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14] It is available as a generic medication.[15][16] In the United Kingdom, it is available over the counter.[17] Most of the active pharmaceutical ingredient, sildenafil citrate, is produced in Pfizer's Ringaskiddy complex in County Cork, Ireland, which is Pfizer's largest production facility outside of the United States.[18]

Medical uses

 
Pfizer Viagra tablet in the trademark blue diamond shape

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete sexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for males with diabetes mellitus.[19]

Antidepressant-associated sexual dysfunction

Tentative evidence suggests that sildenafil may help males who experience antidepressant-induced erectile dysfunction.[20]

Pulmonary hypertension

While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects.[21]

Raynaud's phenomenon

Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud's phenomenon;[9][22] these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes.[9] As of 2016, their role more generally in Raynaud's was not clear.[22]

High-altitude pulmonary edema

Sildenafil has been studied for high-altitude pulmonary edema, but its use is currently not recommended for that indication.[23]

Adverse effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion, and impaired vision, including photophobia and blurred vision.[4] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[24] This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have a minor level of selectivity for PDE6, which is the phosphodiesterase found in the retina. Patients thus taking the drug may experience colorvision abnormalities. Some complained of blurriness and loss of peripheral vision. In July 2005, the U.S. Food and Drug Administration (FDA) updated labeling for Cialis, Levitra and Viagra to reflect a small number of post-marketing reports of sudden vision loss, while acknowledging that "...it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes, or to a combination of these problems."[25] A careful review of pooled data from clinical trials containing well documented information about the dose and duration of exposure to the drug for a large number of patients, yields no evidence for an increased risk of non-arteritic anterior ischemic optic neuropathy or other adverse ocular events associated with PDE-5 inhibitor use.[26]

Rare but serious adverse effects found through postmarketing surveillance include prolonged erections, severe low blood pressure, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.[4] 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.[27]

Interactions

Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours.[4] Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine, both of which can also lead to prolonged plasma half-life levels.[28]

The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.[29]

Contraindications

Contraindications include:[4]

Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.[31]

Nonmedical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[32] 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.[33] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[33] or permanently increases penis size.[34] Studies on the effects of sildenafil when used recreationally are limited, but suggest it has little effect when used by those who do not have erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the postejaculatory refractory time.[35] This study also noted a significant placebo effect in the control group.[35]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[36] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[33] 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".[33] Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal.[33]

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 sildenafil helps treat jet lag recovery in hamsters.[37][38]

Sports

Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe it will enhance their performances.[39][40]

Analogs

Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter.[41] These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles.[42] 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 analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market.[43]

The U.S. Food and Drug Administration (FDA) has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil.[44][45][46] Sellers 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 quantified in plasma, serum, or whole blood 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 overdose.[47]

Mechanism of action

 
Crystal structure of human PDE5 with bound sildenafil, PDB entry 1udt[48]

Sildenafil protects 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.[49] 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.

The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase, RhoA, IP3 receptor, phospholipase C, and others.[50] Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.[50]

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 increased penile response to sexual stimulation.[49][51] 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 broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4 (major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafil's action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). 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.[52]

Route of administration

  • When taken orally, sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).[53]
  • Sublingual use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.[10]

There are also mouth spray preparations of sildenafil for faster onset of action.

Chemical synthesis

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

  1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
  2. Hydrolysis with aqueous sodium hydroxide (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 group
  6. Acylation with 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonation to the chlorosulfonyl derivative
  9. Condensation with 1-methylpiperazine.

History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists led by Simon Campbell[55] 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).[56] The first clinical trials were conducted in Morriston Hospital in Swansea.[57] Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina, but it could induce marked penile erections.[58][59] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example of drug repositioning.[60][61] The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 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.[62] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.[63][globalize]

Counterfeits

Further information: Counterfeit medications

Counterfeit Viagra, despite generally being cheaper,[64] can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetamines, metronidazole, boric acid, and rat poison.[65]

Viagra is one of the world's most counterfeited medicines.[66][67] According to a 2012 Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.[65]

An October 2023 release stated that erectile dysfunction medicines were the most seized drugs by the Interpol[68] accounting for 22% of seizures.[69] International networks may be active.[70][71]

Society and culture

Marketing and sales

 
Bulk bag of counterfeit Viagra
Further information: Medicalisation of sexuality

In the US, even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on 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", often a simple web questionnaire.[72][73] 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", or "blue diamond", as well as various other nicknames.

Viagra and other products for sexual dysfunction, termed sexuopharmaceuticals, proliferated new types of specialised marketing for such products based on neoliberal rhetoric framing viewers as "responsible informed, aspirational sexual subjects".[74] Viagra and similar prescription pharmaceuticals were promoted by images in media to the extent of becoming a cultural icon, at the time a relatively new phenomenon known to be permitted only in the United States and New Zealand and which is believed to of significantly contributed to norms regarding male sexuality.[75] One author notes that although the effect of Viagra is only limited to penile blood vessels, advertisements routinely use imagery of couples hugging, smiling and dancing, with the author claiming that pharmaceutical companies were deceptive in the use of such advertisements.[76]

In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills.[77] By 2007, Viagra's global share had plunged to about 50%[78] 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.[79][80] In 2008, the FDA forced Pfizer to remove Viva Cruiser, an advergame for Viagra, from appearing on Forbes.com, after the game failed to disclose risk information about the drug.[81][82]

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. Males between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[83] In 2017, the Medicines and Healthcare products Regulatory Agency (MHRA) enacted legislation that expanded this nationwide,[84] allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills.[85] The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.

On 6 May 2013, Pfizer, which manufactures Viagra, told the Associated Press they will begin selling the drug directly to people on its website.[86]

Pfizer's patents on Viagra expired outside the US in 2012; in the US they were set to expire, but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017.[87][88] In December 2017, Pfizer released its own generic version of Viagra.[89][90]

As of 2018, the U.S. Food and Drug Administration has approved fifteen drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India. This is likely to lead to dramatic price reductions.[91][92]

Regional issues

United States

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[93] This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013.[94] Health care providers may prescribe generic sildenafil for erectile dysfunction.[95] For a time, the generic was not available in the same dosages as branded Viagra, so using dosages typically required for treating ED required patients to take multiple pills.[95]

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[96] This would be marketed as Viagra. This patent was published in 2002 and expired in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.[97] An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.[95]

In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.[95]

Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension.[95] In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and US$37.88.[98] As of 2016 branded pills cost about 50 times more than generic ones.[95]

Brazil

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[99]

Canada

In Canada, Pfizer's patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.[100][101]

On 8 November 2012, the Supreme Court of Canada ruled that Pfizer's patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to 'game' the system in this way. This, in my view, is the key issue in this appeal."[102]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[103][104][105] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[106] However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[107] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[108] Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.[109]

China

Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer's patent claim is not widely enforced.

Egypt

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer's price.[110]

European Union

 
Sildenafil 100 milligram tablets (prescription in the European Union)

Pfizer's patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013.[111][112][113] 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.[114][115]

India

Manufacture and sale of sildenafil citrate drugs known as "generic Viagra" is common in India, where Pfizer's patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).

New Zealand

Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist. It is thought that this reduced sales over the Internet and was safer as males could be referred for medical advice if appropriate.[116]

South Korea

In 1999 South Korea granted two patents to Pfizer related to sildenafil. The first document guaranteed sole production and sale of the substance until 2012, while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014.[117] In 2011 Hanmi Pharmaceutical and CJ CheilJedang launched a suit against the exclusive use patent. The Korean Court system made a ruling against Pfizer in June 2012, allowing for the unhindered domestic production of generic prescription sildenafil.[118]

During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea. This development was credited largely "due to the introduction of generic products." Generic sildenafil became publicly available in May. Sales of PalPal by Hanmi Pharmaceuticals totalled ₩22 billion or about 86% the market share of Viagra that year.[119] By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.[120]

United Kingdom

There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.[121]

In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK,[85] in an attempt to widen availability and reduce demand for counterfeit products.

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External links

  • "Sildenafil". Drug Information Portal. U.S. National Library of Medicine.
  • "Sildenafil citrate". Drug Information Portal. U.S. National Library of Medicine.
  • Viagra at The Periodic Table of Videos (University of Nottingham)

February 16, 2024
sildenafil, viagra, redirects, here, other, uses, viagra, disambiguation, sold, under, brand, name, viagra, among, others, medication, used, treat, erectile, dysfunction, pulmonary, arterial, hypertension, also, sometimes, used, label, treatment, certain, symp. Viagra redirects here For other uses see Viagra disambiguation Sildenafil sold under the brand name Viagra among others is a medication used to treat erectile dysfunction and pulmonary arterial hypertension 4 8 It is also sometimes used off label for the treatment of certain symptoms in secondary Raynaud s phenomenon 9 It is unclear if it is effective for treating sexual dysfunction in females 8 It can be taken orally swallowed by mouth intravenously injection into a vein or through the sublingual route dissolved under the tongue 8 10 Onset when taken orally is typically within twenty minutes and lasts for about two hours 8 SildenafilClinical dataPronunciation s ɪ l ˈ d ɛ n e f ɪ l sil DEN e filTrade namesViagra Revatio othersAHFS Drugs comMonographMedlinePlusa699015License dataEU EMA by INN US DailyMed SildenafilPregnancycategoryAU B1 1 Routes ofadministrationOral tablets intravenous sublingualATC codeG04BE03 WHO Legal statusLegal statusAU S4 Prescription only CA only UK P Pharmacy medicines POM 2 3 US only 4 EU Rx only 5 6 In general Prescription only Pharmacokinetic dataBioavailability41 mean 7 Protein binding 96 MetabolismLiver CYP3A4 major route CYP2C9 minor route MetabolitesN desmethylsildenafil 50 potency for PDE5 Onset of action20 minutesElimination half life3 4 hoursExcretionFeces 80 urine 13 4 IdentifiersIUPAC name 5 2 Ethoxy 5 4 methylpiperazin 1 yl sulfonyl phenyl 1 methyl 3 propyl 1 6 dihydro 6H pyrazolo 4 3 d pyrimidin 7 oneCAS Number139755 83 2 Ycitrate 171599 83 0 YPubChem CID135398744citrate 135413523DrugBankDB00203 Ycitrate DBSALT000347 YChemSpider5023 Ycitrate 56586 YUNII3M7OB98Y7Hcitrate BW9B0ZE037 YKEGGD08514 Ycitrate D02229 YChEBICHEBI 9139 Ycitrate CHEBI 58987 YChEMBLChEMBL192 Ycitrate ChEMBL1737 YPDB ligandVIA PDBe RCSB PDB CompTox Dashboard EPA DTXSID6023579ECHA InfoCard100 122 676Chemical and physical dataFormulaC 22H 30N 6O 4SMolar mass474 58 g mol 13D model JSmol Interactive imageSMILES CCCC1 NN C2 C1N C NC2 O C3 C C CC C3 S O O N4CCN CC4 C OCC CInChI InChI 1S C22H30N6O4S 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 h8 9 14H 5 7 10 13H2 1 4H3 H 23 24 29 NKey BNRNXUUZRGQAQC UHFFFAOYSA N N N Y what is this verify Common side effects include headaches heartburn and flushed skin 8 Caution is advised in those with cardiovascular disease 8 Rare but serious side effects include vision problems hearing loss and prolonged erection priapism that can lead to damage to the penis 8 Sildenafil should not be taken by people on nitrates such as nitroglycerin glycerin trinitrate as this may result in a serious drop in blood pressure 8 Sildenafil should not be taken within four hours of taking an alpha blocker Sildenafil acts by blocking phosphodiesterase 5 PDE5 an enzyme that promotes breakdown of cGMP which regulates blood flow in the penis 8 It requires sexual arousal to work and does not by itself cause or increase sexual arousal 8 It also results in dilation of the blood vessels in the lungs 8 Pfizer originally discovered the medication in 1989 while looking for a treatment for angina 11 It was approved for medical use in the United States and in the European Union in 1998 5 8 11 12 In 2020 it was the 183rd most commonly prescribed medication in the United States with more than 2 million prescriptions 13 14 It is available as a generic medication 15 16 In the United Kingdom it is available over the counter 17 Most of the active pharmaceutical ingredient sildenafil citrate is produced in Pfizer s Ringaskiddy complex in County Cork Ireland which is Pfizer s largest production facility outside of the United States 18 Contents 1 Medical uses 1 1 Sexual dysfunction 1 1 1 Antidepressant associated sexual dysfunction 1 2 Pulmonary hypertension 1 3 Raynaud s phenomenon 1 4 High altitude pulmonary edema 2 Adverse effects 2 1 Interactions 2 2 Contraindications 3 Nonmedical use 3 1 Recreational use 3 2 Jet lag research 3 3 Sports 3 4 Analogs 4 Detection in biological fluids 5 Mechanism of action 6 Route of administration 7 Chemical synthesis 8 History 9 Counterfeits 10 Society and culture 10 1 Marketing and sales 10 2 Regional issues 10 2 1 United States 10 2 2 Brazil 10 2 3 Canada 10 2 4 China 10 2 5 Egypt 10 2 6 European Union 10 2 7 India 10 2 8 New Zealand 10 2 9 South Korea 10 2 10 United Kingdom 11 References 12 External linksMedical uses nbsp Pfizer Viagra tablet in the trademark blue diamond shapeSexual dysfunction The primary indication of sildenafil is treatment of erectile dysfunction inability to sustain a satisfactory erection to complete sexual intercourse Its use is now one of the standard treatments for erectile dysfunction including for males with diabetes mellitus 19 Antidepressant associated sexual dysfunction Tentative evidence suggests that sildenafil may help males who experience antidepressant induced erectile dysfunction 20 Pulmonary hypertension While sildenafil improves some markers of disease in people with pulmonary arterial hypertension it does not appear to affect the risk of death or serious side effects 21 Raynaud s phenomenon Sildenafil and other PDE5 inhibitors are used off label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud s phenomenon 9 22 these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes 9 As of 2016 update their role more generally in Raynaud s was not clear 22 High altitude pulmonary edema Sildenafil has been studied for high altitude pulmonary edema but its use is currently not recommended for that indication 23 Adverse effectsIn clinical trials the most common adverse effects of sildenafil use included headache flushing indigestion nasal congestion and impaired vision including photophobia and blurred vision 4 Some sildenafil users have complained of seeing everything tinted blue cyanopsia 24 This cyanopsia can be explained because Sildenafil while selective for PDE5 does have a minor level of selectivity for PDE6 which is the phosphodiesterase found in the retina Patients thus taking the drug may experience colorvision abnormalities Some complained of blurriness and loss of peripheral vision In July 2005 the U S Food and Drug Administration FDA updated labeling for Cialis Levitra and Viagra to reflect a small number of post marketing reports of sudden vision loss while acknowledging that it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes or to a combination of these problems 25 A careful review of pooled data from clinical trials containing well documented information about the dose and duration of exposure to the drug for a large number of patients yields no evidence for an increased risk of non arteritic anterior ischemic optic neuropathy or other adverse ocular events associated with PDE 5 inhibitor use 26 Rare but serious adverse effects found through postmarketing surveillance include prolonged erections severe low blood pressure myocardial infarction heart attack ventricular arrhythmias stroke increased intraocular pressure and sudden hearing loss 4 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 27 Interactions Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection Protease inhibitors inhibit the metabolism of sildenafil effectively multiplying the plasma levels of sildenafil increasing the incidence and severity of side effects Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours 4 Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine both of which can also lead to prolonged plasma half life levels 28 The use of sildenafil and an a1 blocker typically prescribed for hypertension or for urologic conditions such as benign prostatic hypertrophy at the same time may lead to low blood pressure but this effect does not occur if they are taken at least 4 hours apart 29 Contraindications Contraindications include 4 Concomitant use of nitric oxide donors organic nitrites and nitrates 30 such as nitroglycerin isosorbide mononitrate isosorbide dinitrate sodium nitroprusside alkyl nitrites commonly known as poppers Concomitant use of soluble guanylyl cyclase stimulators such as riociguat Known hypersensitivity to sildenafilSildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors 31 Nonmedical useRecreational use Sildenafil s popularity with young adults has increased over the years 32 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 33 The reasons behind such use include the belief that the drug increases libido improves sexual performance 33 or permanently increases penis size 34 Studies on the effects of sildenafil when used recreationally are limited but suggest it has little effect when used by those who do not have erectile dysfunction In one study a 25 mg dose was shown to cause no significant change in erectile quality but did reduce the postejaculatory refractory time 35 This study also noted a significant placebo effect in the control group 35 Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs 36 Sildenafil is sometimes used to counteract the effects of other substances often illicit 33 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 33 Mixing it with amyl nitrite another vasodilator is particularly dangerous and potentially fatal 33 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 sildenafil helps treat jet lag recovery in hamsters 37 38 Sports Professional athletes have been documented using sildenafil believing the opening of their blood vessels will enrich their muscles In turn they believe it will enhance their performances 39 40 Analogs Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of herbal aphrodisiac products sold over the counter 41 These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed and thus have unknown side effect profiles 42 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 analogs of illegal drugs of abuse rather than analogs of prescription medicines However at least one court case has resulted in a product being taken off the market 43 The U S Food and Drug Administration FDA has banned numerous products claiming to be Eurycoma longifolia that in fact contain only analogs of sildenafil 44 45 46 Sellers of such fake herbals typically respond by just changing the names of their products Detection in biological fluidsSildenafil and or N desmethylsildenafil its major active metabolite may be quantified in plasma serum or whole blood 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 overdose 47 Mechanism of action nbsp Crystal structure of human PDE5 with bound sildenafil PDB entry 1udt 48 Sildenafil protects 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 49 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 The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP dependent protein kinase also known as PKG This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells namely myosin light chain phosphatase RhoA IP3 receptor phospholipase C and others 50 Overall this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium engendering smooth muscle relaxation 50 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 increased penile response to sexual stimulation 49 51 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 broken down in the liver by hepatic metabolism using cytochrome p450 enzymes mainly CYP450 3A4 major route but also by CYP2C9 minor route hepatic isoenzymes The major product of metabolisation by these enzymes is N desmethylated sildenafil which is metabolised further This metabolite also has an affinity for the PDE receptors about 40 of that of sildenafil Thus the metabolite is responsible for about 20 of sildenafil s action Sildenafil is excreted as metabolites predominantly in the feces about 80 of administered oral dose and to a lesser extent in the urine around 13 of the administered oral dose 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 52 Route of administrationWhen taken orally sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes ranging from 12 to 70 minutes 53 Sublingual use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes 10 There are also mouth spray preparations of sildenafil for faster onset of action Chemical synthesisThe preparation steps for synthesis of sildenafil are 54 Methylation of 3 propylpyrazole 5 carboxylic acid ethyl ester with hot dimethyl sulfate Hydrolysis with aqueous sodium hydroxide NaOH to free acid Nitration with oleum fuming nitric acid Carboxamide formation with refluxing thionyl chloride NH4OH Reduction of nitro group to amino group Acylation with 2 ethoxybenzoyl chloride Cyclization Sulfonation to the chlorosulfonyl derivative Condensation with 1 methylpiperazine HistorySildenafil compound UK 92 480 was synthesized by a group of pharmaceutical chemists led by Simon Campbell 55 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 56 The first clinical trials were conducted in Morriston Hospital in Swansea 57 Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina but it could induce marked penile erections 58 59 Pfizer therefore decided to market it for erectile dysfunction rather than for angina this decision became an often cited example of drug repositioning 60 61 The drug was patented in 1996 approved for use in erectile dysfunction by the FDA on 27 March 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 62 It soon became a great success annual sales of Viagra peaked in 2008 at US 1 934 billion 63 globalize CounterfeitsFurther information Counterfeit medications Counterfeit Viagra despite generally being cheaper 64 can contain harmful substances or substances that affect how Viagra works such as blue printer ink amphetamines metronidazole boric acid and rat poison 65 Viagra is one of the world s most counterfeited medicines 66 67 According to a 2012 Pfizer study around 80 of sites claiming to sell Viagra were selling counterfeits 65 An October 2023 release stated that erectile dysfunction medicines were the most seized drugs by the Interpol 68 accounting for 22 of seizures 69 International networks may be active 70 71 Society and cultureMarketing and sales nbsp Bulk bag of counterfeit ViagraFurther information Medicalisation of sexuality In the US even though sildenafil is available only by prescription from a doctor it was advertised directly to consumers on TV famously being endorsed by former United States Senator Bob Dole and football star Pele Numerous sites on the Internet offer Viagra for sale after an online consultation often a simple web questionnaire 72 73 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 or blue diamond as well as various other nicknames Viagra and other products for sexual dysfunction termed sexuopharmaceuticals proliferated new types of specialised marketing for such products based on neoliberal rhetoric framing viewers as responsible informed aspirational sexual subjects 74 Viagra and similar prescription pharmaceuticals were promoted by images in media to the extent of becoming a cultural icon at the time a relatively new phenomenon known to be permitted only in the United States and New Zealand and which is believed to of significantly contributed to norms regarding male sexuality 75 One author notes that although the effect of Viagra is only limited to penile blood vessels advertisements routinely use imagery of couples hugging smiling and dancing with the author claiming that pharmaceutical companies were deceptive in the use of such advertisements 76 In 2000 Viagra sales accounted for 92 of the global market for prescribed erectile dysfunction pills 77 By 2007 Viagra s global share had plunged to about 50 78 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 79 80 In 2008 the FDA forced Pfizer to remove Viva Cruiser an advergame for Viagra from appearing on Forbes com after the game failed to disclose risk information about the drug 81 82 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 Males between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist 83 In 2017 the Medicines and Healthcare products Regulatory Agency MHRA enacted legislation that expanded this nationwide 84 allowing a particular branded formulation of Sildenafil Viagra Connect 50 mg to be sold over the counter and without a prescription throughout the UK from early 2018 While the sale remains subject to a consultation with a pharmacist the other restrictions from the trial have been removed allowing customers over the age of 18 to purchase an unlimited number of pills 85 The decision was made in part to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments On 6 May 2013 Pfizer which manufactures Viagra told the Associated Press they will begin selling the drug directly to people on its website 86 Pfizer s patents on Viagra expired outside the US in 2012 in the US they were set to expire but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017 87 88 In December 2017 Pfizer released its own generic version of Viagra 89 90 As of 2018 update the U S Food and Drug Administration has approved fifteen drug manufacturers to market generic sildenafil in the United States Seven of these companies are based in India This is likely to lead to dramatic price reductions 91 92 Regional issues United States In 1992 Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases 93 This would be marketed as Revatio The patent was published in 1993 and expired in 2012 The patent on Revatio indicated for pulmonary arterial hypertension rather than erectile dysfunction expired in late 2012 Generic versions of this low dose form of sildenafil have been available in the U S from a number of manufacturers including Greenstone Mylan and Watson since early 2013 94 Health care providers may prescribe generic sildenafil for erectile dysfunction 95 For a time the generic was not available in the same dosages as branded Viagra so using dosages typically required for treating ED required patients to take multiple pills 95 In 1994 Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction 96 This would be marketed as Viagra This patent was published in 2002 and expired in 2019 Teva sued to have the latter patent invalidated but Pfizer prevailed in an August 2011 federal district court case 97 An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017 95 In the United States Pfizer received two patents for sildenafil one for its indication to treat cardiovascular disease marketed as Revatio and another for its indication to treat erectile dysfunction marketed as Viagra The substance is the same under both trade names 95 Sildenafil is available as a generic drug in the United States labeled for pulmonary arterial hypertension 95 In the United States as of 2015 update the branded 50 mg pill cost is between 25 17 and US 37 88 98 As of 2016 update branded pills cost about 50 times more than generic ones 95 Brazil Pfizer s patent on sildenafil citrate expired in Brazil in 2010 99 Canada In Canada Pfizer s patent 2 324 324 for Revatio sildenafil used to treat pulmonary hypertension was found invalid by the Federal Court in June 2010 on an application by Ratiopharm Inc 100 101 On 8 November 2012 the Supreme Court of Canada ruled that Pfizer s patent 2 163 446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application The decision Teva Canada Ltd v Pfizer Canada Inc pointed to section 27 3 b of The Patent Act which requires that disclosure must include sufficient information to enable any person skilled in the art or science to which it pertains to produce it It added further As a matter of policy and sound statutory interpretation patentees cannot be allowed to game the system in this way This in my view is the key issue in this appeal 102 Teva Canada launched Novo Sildenafil a generic version of Viagra on the day the Supreme Court of Canada released its decision 103 104 105 To remain competitive Pfizer then reduced the price of Viagra in Canada 106 However on 9 November 2012 Pfizer filed a motion for a re hearing of the appeal in the Supreme Court of Canada 107 on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent 108 Finally on 22 April 2013 the Supreme Court of Canada invalidated Pfizer s patent altogether 109 China Manufacture and sale of sildenafil citrate drugs is common in China where Pfizer s patent claim is not widely enforced Egypt Egypt approved Viagra for sale in 2002 but soon afterwards allowed local companies to produce generic versions of the drug citing the interests of poor people who would not be able to afford Pfizer s price 110 European Union nbsp Sildenafil 100 milligram tablets prescription in the European Union Pfizer s patent on sildenafil citrate expired in some member countries of the EU Austria Denmark France Germany Ireland Italy The Netherlands Spain Sweden the United Kingdom and Switzerland on 21 June 2013 111 112 113 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 114 115 India Manufacture and sale of sildenafil citrate drugs known as generic Viagra is common in India where Pfizer s patent claim does not apply Trade names include Kamagra Ajanta Pharma Silagra Cipla Edegra Sun Pharmaceutical Penegra Zydus Cadila Manly Cooper Pharma and Zenegra Alkem Laboratories New Zealand Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist It is thought that this reduced sales over the Internet and was safer as males could be referred for medical advice if appropriate 116 South Korea In 1999 South Korea granted two patents to Pfizer related to sildenafil The first document guaranteed sole production and sale of the substance until 2012 while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014 117 In 2011 Hanmi Pharmaceutical and CJ CheilJedang launched a suit against the exclusive use patent The Korean Court system made a ruling against Pfizer in June 2012 allowing for the unhindered domestic production of generic prescription sildenafil 118 During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea This development was credited largely due to the introduction of generic products Generic sildenafil became publicly available in May Sales of PalPal by Hanmi Pharmaceuticals totalled 22 billion or about 86 the market share of Viagra that year 119 By 2017 there were over 50 generic sildenafil pills available During that year Viagra sales slumped to 38 that of Palpal 120 United Kingdom There were 2 958 199 prescriptions for Sildenafil in 2016 in England compared with 1 042 431 in 2006 121 In 2018 Viagra Connect a particular formulation of Sildenafil marketed by Pfizer became available for sale without a prescription in the UK 85 in an attempt to widen availability and reduce demand for counterfeit products References Sildenafil Use During Pregnancy Drugs com 7 October 2019 Retrieved 6 October 2020 Viagra 25mg film coated tablets Summary of Product Characteristics SmPC emc 7 August 2020 Retrieved 6 October 2020 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Retrieved 28 December 2021 Viagra prescriptions almost triple in a decade Pharmaceutical Journal 21 August 2017 Retrieved 8 October 2017 permanent dead link External linksSildenafil at Wikipedia s sister projects nbsp Definitions from Wiktionary nbsp Media from Commons nbsp News from Wikinews nbsp Quotations from Wikiquote nbsp Texts from Wikisource nbsp Textbooks from Wikibooks nbsp Resources from Wikiversity Sildenafil Drug Information Portal U S National Library of Medicine Sildenafil citrate Drug Information Portal U S National Library of Medicine Viagra at The Periodic Table of Videos University of Nottingham Portals nbsp Chemistry nbsp Medicine Retrieved from https en wikipedia org w index php title Sildenafil amp oldid 1193290963, wikipedia, wiki, book, books, library,

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