Sildenafil

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

Sildenafil

Systematic (IUPAC) name
1-[4-ethoxy-3-(6,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine
Clinical data
Trade names	Viagra, Revatio, others
AHFS/Drugs.com	monograph
MedlinePlus	a699015
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: B (No risk in non-human studies)
Legal status	Rx-only
Routes of administration	Oral, IV
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 Y
ATC code	G04BE03 (WHO)
PubChem	CID: 5281023
DrugBank	DB00203 Y
ChemSpider	56586 Y
UNII	3M7OB98Y7H Y
KEGG	D08514 Y
ChEBI	CHEBI:58987 Y
ChEMBL	CHEMBL1737 N
PDB ligand ID	VIA (PDBe, RCSB PDB)
Chemical data
Formula	C22H30N6O4S
Molecular mass	base: 474.6 g/mol
SMILES CN1CCN(S(=O)(C2=CC=C(OCC)C(C3=NC4=C(N(C)N=C4CCC)C(N3)=O)=C2)=O)CC1
InChI InChI=1S/C22H30N6O4S.C6H8O7/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28;7-3(8)1-6(13,5(11)12)2-4(9)10/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12) Y Key:DEIYFTQMQPDXOT-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Sildenafil, sold as Viagra and other trade names, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. Its effectiveness for treating sexual dysfunction in women has not been demonstrated.

Common side effects include headaches and heart burn, as well as flushed skin. Caution is advised in those who have cardiovascular disease. Rare but serious side effects include prolonged erections, which can lead to damage to the penis, and sudden-onset hearing loss. Sildenafil should not be taken by people who take nitrates such as nitroglycerin, as this may result in a severe and potentially fatal drop in blood pressure.

It acts by inhibiting cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis.

It was originally discovered by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett. Since becoming available in 1998, sildenafil has been a common treatment for erectile dysfunction; its primary competitors are tadalafil (Cialis) and vardenafil (Levitra).

Medical uses

Viagra

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 including for those with diabetes mellitus.

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 as of 2014.

Antidepressant-associated sexual dysfunction

There is tentative evidence that among men who experience antidepressant induced erectile dysfunction sildenafil may help.

Altitude sickness

Sildenafil appears to improve some risk factors for high-altitude pulmonary edema but it is unclear whether or not it affects the rate of the condition itself as of 2008.

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. Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). Some complained of blurriness and loss of peripheral vision. In July 2005, the FDA found that sildenafil could lead to vision impairment in rare cases and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy. 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. 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.

Interactions

Care should be exercised by people who 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. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25-mg dose every 48 hours. 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.

The use of sildenafil and an alpha blocker at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.

Contraindications

Contraindications include:

• When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")
• In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors
• Severe hepatic impairment (decreased liver function)
• Severe impairment in renal function
• Hypotension (low blood pressure)
• Recent stroke or heart attack
• Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

Nonmedical use

Recreational use

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

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

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.

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.

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, thus has an unknown side-effect profile. 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.

The US FDA has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil. 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.

Mechanism of action

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

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. Robert F. Furchgott, Ferid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. 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.

Route of administration

• When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).
• Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.

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

Chemical synthesis

The preparation steps for synthesis of sildenafil are:

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

History

Origins

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea. 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. 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 FDA 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. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, but only Andrew Bell, David Brown, and Nicholas Terrett are listed on the original composition of matter patent.

Marketing and sales

File:CBP with bag of seized counterfeit Viagra.jpg

Bulk bag of counterfeit Viagra

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. The Viagra name has become so well known, 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.

In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills. By 2007, Viagra's global share had plunged to about 50% 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.

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

On May 6, 2013, Pfizer, which manufacturers Viagra, told the Associated Press they will begin selling the drug directly to patients on its website.

Patents

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. 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.

United States

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases. This patent was published in 1993 and expired in 2012. In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.

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. No legal barrier exists to doctors prescribing this form of sildenafil "off label" for erectile dysfunction, although the dosage typically required for treating ED requires patients to take multiple pills.

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.

On November 8, 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."

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

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), and Zenegra (Alkem Laboratories).

China

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

Other countries

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.

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

External links

• Official Viagra Website
• Official Viagra UK Website
• Official Revatio Website
• prescribing information for Viagra and prescribing information for Revatio from Pfizer
• FDA Information
• MedlinePLUS information, including side effects
• U.S. National Library of Medicine: Drug Information Portal – Sildenafil
• Viagra at The Periodic Table of Videos (University of Nottingham)