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Sildenafil, sold as the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.
Common side effects include headaches, heartburn, and flushed skin.
Sildenafil acts by blocking phosphodiesterase 5 (PDE 5 ), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis.
Pfizer originally discovered the medication in 1989 while looking for a treatment for heart related chest pain.
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
3 Nonmedical use
3.1 Recreational use
3.2 Jet lag research
4 Detection in biological fluids
5 Mechanism of action
6 Route of administration
7 Chemical synthesis
9 Society and culture
9.1 Marketing and sales
9.3 Regional issues
9.3.1 European Union
9.3.2 United Kingdom
9.3.3 United States
9.3.7 New Zealand
9.3.8 Other countries
11 External links
Pfizer Viagra tablet in the trademark blue diamond shape
The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.
Antidepressant-associated sexual dysfunction
Tentative evidence suggests that sildenafil may help men who experience antidepressant -induced erectile dysfunction.
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
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 ;
High-altitude pulmonary edema
Sildenafil has been studied for high-altitude pulmonary edema but its use is currently not recommended for that indication.
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.
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.
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. 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 α 1 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.
Contraindications include: : 11
Concomitant use of nitric oxide donors, organic nitrites and nitrates, such as:
alkyl nitrites (commonly known as ” poppers “)
Concomitant use of soluble guanylyl cyclase stimulators, such as riociguat
Known hypersensitivity to sildenafil
Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors
Sildenafil’s popularity with young adults has increased over the years.
Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.
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.
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.
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.
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.
The preparation steps for synthesis of sildenafil are:
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 /NH 4 OH
Reduction of nitro group to amino group
Acylation with 2-ethoxybenzoyl chloride
Sulfonation to the chlorosulfonyl derivative
Condensation with 1-methylpiperazine.
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.
Society and culture
Marketing and sales
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.
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. 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 patients on its website.
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.
As of 2018, the U.S. Food and Drug Administration has approved 15 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.
Further information: Counterfeit medications
Counterfeit Viagra, despite generally being cheaper,
Viagra is one of the world’s most counterfeited medicines.
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.
There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.
In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK , in an attempt to widen availability and reduce demand for counterfeit products.
Sildenafil is available as a generic drug in the United States, labelled for pulmonary arterial hypertension.
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.
In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.
In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.
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 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.”
Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.
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 ).
Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer’s patent claim is not widely enforced.
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 men could be referred for medical advice if appropriate.
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.
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