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Sildenafil

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

Sildenafil
Clinical data
Pronunciation/sɪlˈdɛnəfɪl/sil-DEN-ə-fil
Trade namesViagra, others
AHFS/DrugsMonograph
MedlinePlusa699015
License data
Pregnancy
category
Routes of
administration		Oral,intravenous,sublingual
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability41% (mean)[7]
Protein binding~96%
MetabolismLiver:CYP3A4(major route),CYP2C9(minor route)
MetabolitesN-desmethylsildenafil (~50% potency for PDE5)
Onset of action20 minutes
Eliminationhalf-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
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.122.676Edit this at Wikidata
Chemical and physical data
FormulaC22H30N6O4S
Molar mass474.58g·mol−1
3D model (JSmol)
  • 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
☒NcheckY(what is this?)(verify)

Sildenafil,sold under the brand nameViagra,among others, is amedicationused to treaterectile dysfunctionandpulmonary arterial hypertension.[4][8]It is also sometimes usedoff-labelfor the treatment of certain symptoms in secondaryRaynaud's phenomenon.[9]It is unclear if it is effective for treating sexual dysfunction in females.[8]It can be takenorally(swallowed by mouth),intravenously(injection into a vein), or through thesublingual route(dissolved under the tongue).[8][10]Onset when taken orally is typically within twenty minutes and lasts for about two hours.[8]

Common side effects includeheadaches,heartburn,and flushed skin.[8]Caution is advised in those withcardiovascular disease.[8]Rare but serious side effects include vision problems,hearing loss,andprolonged erection(priapism) that can lead to damage to thepenis.[8]Sildenafil should not be taken by people onnitric oxide donorssuch asnitroglycerin(glycerin trinitrate), as this may result in a serious drop inblood pressure.[8]

Sildenafil acts by blockingphosphodiesterase 5(PDE5), anenzymethat promotes breakdown ofcGMP,which regulates blood flow in the penis.[8]It requiressexual arousalto 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]

Pfizeroriginally discovered the medication in 1989 while looking for a treatment forangina.[11]It was approved for medical use in the United States and in the European Union in 1998.[5][8][11][12]In 2021, it was the 157th most commonly prescribed medication in the United States, with more than 3million prescriptions.[13][14]It is available as ageneric medication.[15][16]In the United Kingdom, it is availableover the counter.[17]

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 completesexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for males withdiabetes mellitus.[18]

Antidepressant-associated sexual dysfunction

Tentative evidence suggests that sildenafil may help males who experienceantidepressant-inducederectile dysfunction.[19]

Pulmonary hypertension

While sildenafil improves some markers of disease in people withpulmonary arterial hypertension,it does not appear to affect the risk of death or serious side effects.[20]

Raynaud's phenomenon

Sildenafil and otherPDE5 inhibitorsare used off-label to alleviatevasospasmand treat severe ischemia and ulcers in fingers and toes for people with secondaryRaynaud's phenomenon;[9][21]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.[21]

High-altitude pulmonary edema

Sildenafil has been studied forhigh-altitude pulmonary edema,but its use is currently not recommended for that indication.[22]

Adverse effects

Inclinical trials,the most commonadverse effectsof sildenafil use includedheadache,flushing,indigestion,nasal congestion,and impaired vision, includingphotophobiaand blurred vision.[4]Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[23]This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have some affinity 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 ofperipheral vision.In July 2005, the USFood 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."[24]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 ofnon-arteritic anterior ischemic optic neuropathyor other adverse ocular events associated with PDE-5 inhibitor use.[25]

Rare but serious adverse effects found throughpostmarketing surveillanceincludeprolonged erections,severelow blood pressure,myocardial infarction(heart attack),ventricular arrhythmias,stroke,increasedintraocular pressure,and suddenhearing loss.[4]In October 2007, the FDA announced that the labeling for allPDE5inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.[26]

Interactions

Care should be exercised by people who are also takingprotease inhibitorsfor the treatment ofHIV 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 includeerythromycinandcimetidine,both of which can also lead to prolonged plasma half-life levels.[27]

The use of sildenafil and anα1blocker(typically prescribed forhypertensionor for urologic conditions, such asbenign 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.[28]

Contraindications

Contraindicationsinclude:[4]

Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.[30]

Nonmedical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[31]Sildenafil's brand name, Viagra, is widely recognized in popular culture, and the drug's association with treating erectile dysfunction has led to its recreational use.[32]The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[32]or permanently increases penis size.[33]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 postejaculatoryrefractory time.[34]This study also noted a significantplacebo effectin the control group.[34]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[35]Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[32]Some users mix it withmethylenedioxymethamphetamine(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,' "" hammerheading, "or" trail mix ".[32]Mi xing it withamyl nitrite,anothervasodilator,is particularly dangerous and potentially fatal.[32]

Jet lag research

The 2007Ig Nobel Prizein aviation went to Patricia V. Agostino, Santiago A. Plano, andDiego A. GolombekofUniversidad Nacional de Quilmes,Argentina, for their discovery that sildenafil helps treatjet lagrecovery inhamsters.[36][37]

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.[38][39]

Analogs

Acetildenafiland other syntheticstructural analogsof sildenafil which arePDE5 inhibitorshave been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter.[40]These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles.[41]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.[42]

The USFood and Drug Administration(FDA) has banned numerous products claiming to beEurycoma longifoliathat, in fact, contain only analogs of sildenafil.[43][44][45]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.[46]

Mechanism of action

Crystal structure of human PDE5 with bound sildenafil, PDB entry1udt[47]

Sildenafil protectscyclic guanosine monophosphate(cGMP) from degradation bycGMP-specific phosphodiesterase type 5(PDE5) in thecorpus cavernosum.Nitric oxide(NO) in the corpus cavernosum of the penis binds toguanylate cyclasereceptors, which results in increased levels of cGMP, leading tosmooth musclerelaxation (vasodilation) of the intimal cushions of thehelicine arteries.This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection.[48]Robert F. Furchgott,Ferid Murad,andLouis Ignarrowon theNobel Prize in Physiology or Medicinein 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 enzymeCGMP-dependent protein kinase,also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namelymyosin light chain phosphatase,RhoA,IP3 receptor,phospholipase C,and others.[49]Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.[49]

Sildenafil is a potent and selective inhibitor ofcGMP-specific phosphodiesterase type 5(PDE5), which is responsible for degradation of cGMP in thecorpus 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.[48][50]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 includetadalafil(Cialis) andvardenafil(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.[51]

Route of administration

  • When takenorally,sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).[52]
  • Sublingualuse of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.[10]

Chemical synthesis

The preparation steps for synthesis of sildenafil are:[53]

  1. Methylationof 3-propylpyrazole-5-carboxylic acid ethylesterwith hotdimethyl sulfate
  2. Hydrolysiswithaqueoussodium hydroxide(NaOH) to freeacid
  3. Nitrationwitholeum/fumingnitric acid
  4. Carboxamideformation withreflu xingthionyl chloride/NH4OH
  5. Reductionofnitro grouptoamino group
  6. Acylationwith 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonationto the chlorosulfonyl derivative
  9. Condensationwith 1-methylpiperazine.

History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists led bySimon Campbell[54]working at Pfizer'sSandwich, Kent,research facility in England. It was initially studied for use inhypertension(high blood pressure) andangina pectoris(a symptom ofischaemic heart disease).[55]The first clinical trials were conducted inMorriston HospitalinSwansea.[56]Phase Iclinical trialsunder the direction ofIan Osterlohsuggested the drug had little effect on angina, but it could induce marked penileerections.[57][58]Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example ofdrug repositioning.[59][60]The drug waspatentedin 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.[61]It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.[62][globalize]

Counterfeits

Further information:Counterfeit medications

Counterfeit Viagra, despite generally being cheaper,[63]can contain harmful substances or substances that affect how Viagra works, such as blue printer ink,amphetamines,metronidazole,boric acid,andrat poison.[64]

Viagra is one of the world's most counterfeited medicines.[65][66]According to a 2012 Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.[64]

An October 2023 release stated that erectile dysfunction medicines were the most seized drugs by theInterpol[67]accounting for 22% of seizures.[68]International networks may be active.[69][70]

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 formerUnited States SenatorBob DoleandfootballstarPelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire.[71][72]The Viagra name has become so well known that many fakeaphrodisiacsnow 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, termedsexuopharmaceuticals,proliferated new types of specialised marketing for such products.[73]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 have significantly contributed to norms regarding male sexuality.[74]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.[75]

In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills.[76]By 2007, Viagra's global share had plunged to about 50%[77]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.[78][79]In 2008, the FDA forced Pfizer to removeViva Cruiser,anadvergamefor Viagra, from appearing onForbes,after the game failed to disclose risk information about the drug.[80][81]

In February 2007, it was announced thatBoots,the UK pharmacy chain, would tryover-the-countersales of Viagra in stores inManchester, England.Males between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with apharmacist.[82]In 2017, theMedicines and Healthcare products Regulatory Agency(MHRA) enacted legislation that expanded this nationwide,[83]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.[84]The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.

In May 2013,Pfizer,which manufactures Viagra, told theAssociated Pressthey will begin selling the drug directly to people on its website.[85]

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.[86][87]In December 2017, Pfizer released its own generic version of Viagra.[88][89]

As of 2018,the USFood and Drug Administrationhas approved fifteen drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India.[90][91]

Regional issues

United States

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[92]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 versionsof this low-dose form of sildenafil have been available in the US from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013.[93]Health care providers may prescribe generic sildenafil for erectile dysfunction.[94]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.[94]

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[95]This would be marketed as Viagra. This patent was published in 2002 and expired in 2019.Tevasued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.[96]An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.[94]

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 brand names.[94]

Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension.[94]

In the US, Revatio and Viagra are marketed byViatrisafter Upjohn was spun off from Pfizer.[97][98][99][100]

Brazil

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[101]

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 byRatiopharmInc.[102][103]

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."[104]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[105][106][107]To remain competitive, Pfizer then reduced the price of Viagra in Canada.[108]However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[109]on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[110]Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.[111]

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.[112]

European Union

Sildenafil 100 milligram tablets (prescription in the European Union)

Pfizer's patent on sildenafil citrate expired in some member countries of the European Union, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom, and Switzerland in June 2013.[113][114][115]A UK patent held by Pfizer on the use ofPDE5 inhibitors(see below) as treatment of impotence was invalidated in 2000 because ofobviousness;this decision was upheld on appeal in 2002.[116][117]

India

Manufacture and sale of sildenafil citrate drugs known as "generic Viagra" is common in India, where Pfizer's patent claim does not apply. Brand 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.[118]

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.[119]In 2011Hanmi PharmaceuticalandCJ CheilJedanglaunched 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.[120]

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.[121]By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.[122]

United Kingdom

There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.[123]

In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK,[84]in an attempt to widen availability and reduce demand for counterfeit products.

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