Sildenafil

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"Viagra" redirects here. For other uses, see Viagra (disambiguation).
Sildenafil
Sildenafil.svg
Sildenafil-from-xtal-3D-balls.png
Systematic (IUPAC) name
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-
7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)
phenylsulfonyl]-4-methylpiperazine
Clinical data
Trade names Viagra, Revatio, others
AHFS/Drugs.com monograph
MedlinePlus a699015
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic (mostly CYP3A4, also CYP2C9)
Half-life 3 to 4 hours
Excretion Fecal (80%) and renal (around 13%)
Identifiers
CAS number 139755-83-2 YesY
ATC code G04BE03
PubChem CID 5281023
DrugBank DB00203
ChemSpider 56586 YesY
UNII 3M7OB98Y7H YesY
KEGG D08514 YesY
ChEBI CHEBI:58987 YesY
ChEMBL CHEMBL1737 N
PDB ligand ID VIA (PDBe, RCSB PDB)
Chemical data
Formula C22H30N6O4S 
Mol. mass base: 474.6 g/mol
 N (what is this?)  (verify)

Sildenafil, sold as Viagra, Revatio and under various other trade names often in the citrate salt, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was originally discovered by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett.[1][2] It acts by inhibiting cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).

Medical uses

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.[3]

People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation.[4] Following up reports from 1999,[5] the same researchers found that sildenafil improved sexual function in female patients on antidepressants as well.[6]

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the United States Food and Drug Administration (FDA), and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.[7]

Altitude sickness

Sildenafil has been shown to be useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers.[8][9] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.[10]

Dosage

Viagra

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

The dosage for pulmonary arterial hypertension (Revatio) is three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.[11]

Adverse effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision.[12] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[13] 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[14] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[15] Rare but serious adverse effects found through postmarketing surveillance include priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.[12] As a result of these postmarketing reports, in October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.[16]

Interactions

Care should be exercised by patients that are also taking protease inhibitors for the treatment of HIV. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25 mg dose every 48 hours.[17] 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.

Concomitant use of sildenafil and an alpha blocker may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.[18]

Contraindications

Contraindications include:[12](p11)

Non-medical use

Recreational use

Sildenafil's popularity with young adults has increased over the years.[20] 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.[21] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[21] or permanently increases penis size.[22] Studies on the effects of viagra when used recreationally are limited, but suggest that it has little effect when used by those not suffering from erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the post-ejaculatory refractory time.[23] This study also noted a significant placebo effect in the control group.[23]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[24][25] The scale of unprescribed sildenafil consumption is estimated to exceed the legitimate use by Dutch scientists using sewage epidemiology. They estimated that over 60% of the sildenafil consumed in the three Dutch cities could not be explained by legitimate dispensing records.[26] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[21] 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."[21] Mixing with amyl nitrite is particularly dangerous and potentially fatal.[21]

Jet lag research

The 2007 Ig Nobel Prize in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina for their discovery that Viagra helps treat jet lag recovery in hamsters.[27] Their research was published in the Proceedings of the National Academy of Sciences.[28]

Use in sports

Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe that it will enhance their performance.[29][30]

Cut flowers

Israeli and Australian researchers discovered that 1 mg of the drug dissolved in a vase of water can extend the shelf life of cut flowers, making them stand up straight for up to a week beyond their natural life span. The drug also slows down plant ripening; tests were done strawberries, legumes, roses, carnations, broccoli, and other perishables. Viagra increases the vase life of the flowers by slowing the breakdown of cGMP by cGMP-specific phosphodiesterase type 5. The Viagra acts on the cGMP in a fashion similar to nitric oxide (which also slows down the ripening process), but was found to be easier to use with cut flowers.[31][32]

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.[33] This class of analogs has not undergone any of the rigorous testing that drugs like sildenafil have passed, and, thus, has an unknown side-effect profile.[34] Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.[35]

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

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantitated in plasma, serum or whole blood to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.[39]

Mechanism of action

Crystal structure of human PDE5 with bound sildenafil. PDB entry 1udt[40]

The mechanism of action of sildenafil involves the protection of cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection.[41] 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.[41] 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 (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 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.[42]

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:[43]

  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.[44] Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.[2][45] 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.[46] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.[47]

The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, however only Andrew Bell, David Brown, and Nicholas Terrett are listed on the original composition of matter patent.[1]

Marketing and sales

Bulk bag of counterfeit Viagra

Even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on U.S. TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", often a simple web questionnaire.[48][49] The "Viagra" name has become so well known that many fake aphrodisiacs now call themselves "herbal viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", "Blue Diamond" as well as various other nicknames.

In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills.[50] By 2007, Viagra's global share had plunged to about 50 percent[51] 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.[52][53]

In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[54]

On May 6, 2013, Pfizer, who manufacturers Viagra, told The Associated Press that they will begin selling the drug directly to patients on its website.[55]

Coffee

In 2008/9, reports[56] emerged of police and other authorities in Malaysia seizing sachets of coffee laced with sildenafil. Numerous brands tested were found to contain it, and were removed from sale.

Patent issues and expirations

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, United Kingdom as well as Switzerland on 21 June 2013.[57][58][59] 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.[60][61]

United States

In 1992 Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[62] 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.[63] 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.[64]

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.[65] There is no legal barrier 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.[66][67]

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."[68]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[69][70][71] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[72] However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[73] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[74] Finally, on April 22, 2013, The Supreme Court of Canada invalidated Pfizer's patent altogether.[75]

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 known as "generic viagra" 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.[76]

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[77]

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  2. ^ a b Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (June 1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int. J. Impot. Res. 8 (2): 47–52. PMID 8858389. 
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