what is sildenafil

What is Sildenafil?

Sildenafil, sold under the brand name Viagra, among others, to treat erectile dysfunction and pulmonary arterial hypertension, is used to treat sexual dysfunction in women, but does not work for sexual dysfunction alone. It is taken by mouth or in the veins; onset is typically within twenty minutes, lasting about two hours.

Common side effects of Viagra are headache, flushing of the face, stuffy nose, dizziness, back pain, diarrhea, indigestion, upset stomach, nausea, vomiting, muscle ache, tiredness, weakness, facial flushing, chest discomfort, shortness of breath, irregular heartbeat, fainting, blurred or double visions, tingling, numbness, itching, swelling of hands, feet, lips, tongue, throat, neck, breasts, abdomen, lower back, upper arms, legs, or genitals. These symptoms usually go away after about 30 minutes. In rare cases, they may last longer. If any of these effects persist or worsen, tell your doctor immediately.

Viagra works by increasing levels of cyclic guanosine monophosphate (cGMP) in the body. It increases the volume of oxygenated red cells in the bloodstream. It also causes vasodilation (dilated veins).

Pfizer discovered Sildenafil in 1989 while searching for a cure for heart-linked chest pains. They were granted approval for medical use in the U.S. and E.U. in 1998. In 2017 it was the 217th most commonly prescribed drug in the U.S., with 2.2 million prescriptions. It is also available OTC in the U.K. Most of the active pharmaceutical ingredient (API) in SILDENAFIL CITRATE is manufactured in Pfizer’s Ringaskiddy plant in County Cork, Ireland.

Medical uses

Sexual dysfunction

Sildenafil citrate is used primarily to treat erectile dysfunc­tion (impotence) in diabetic and non-diabetic patients.

Antidepressant-associated sexual dysfunction

There is tentative evidence suggesting that Sildenafil might be helpful for men experiencing antidepressants-induced erectile dysfunc­tion.

Pulmonary hypertension

Sildenafil improves specific disease markers in patients with pulmonary arterial hyer­tension (PAH) but doesn’t seem to improve survival or cause any serious adverse events.

Raynaud’s phenomenon

Sildenafil and another phosphodiesterase type 5 (PDE5) inhibitors are commonly prescribed to treat erectile dysfunction and pulmonary arterial hypertension but also may help treat vasospasms associated with Raynaud’s disease. They are effective for mild cases of Raynaud’s syndrome and are sometimes recommended for patients who experience recurrent attacks despite treatment with calcium channel blockers.[4] However, they have limited usefulness for advanced cases of Raynaud’s syndrome.

High-altitude pulmonary edema

Sildenafile citrate has been studied for high altitude pulmonary edema (HAPE), but its use is currently discouraged because of concerns regarding side effects.

Adverse effects

In clinical trials, one of the most commonly reported side effects was a headache, occurring in about 20% of patients. Other side effects include flushes, facial redness, diarrhea, dyspepsia, rhinitis, sinusitis, back pain, myalgia, arthralgia, asthenia, dizziness, hypotension, syncope, nausea, vomiting, abdominal cramps, pruritus, rash, urticaria, angioedema, chest discomfort, cough, epistaxis, eye irritation, dry mouth, fever, flu-like symptoms, heartburn, jaw ache, insomnia, lacrimation, limb pain, muscle spasms, musculoskeletal pain, nervousness, palpitations, paresthesia, pharyngolaryngeal pain, prostration, restlessness, shortness of breath, sweating, tachycardia, tremor, vertigo, weakness, weight gain, and xerostomia.

Rarely serious side effects may occur. These include prolonged erectile dysfunction, low blood pressure, heart attacks, strokes, ventricular arrhythmia, and sudden hearing loss. In October 2007, Pfizer issued a new label for its Viagra pill that requires patients to be warned of the possibility of sudden hearing loss.

Interactions

Care should be taken by those who are also taking proteases to treat HIV infections. Protease Inhibitor drugs inhibit the breakdown of Sildenafile, effectively doubling the amount of Sildenafil in your bloodstream. When used along with other medications that affect the analysis of Sildnafile (such as Erythromycin), these drugs may cause an increase in Sildenafile levels, leading to increased toxicity. Patients taking these drugs are advised to take only one pill daily throughout the day.

If you take Viagra and an alpha one blocker (e.g., tamsulosin) simultaneously, there might be some side effects, but these don’t happen if you take them at least four hours apart.

Contraindications

Contraindications include:

 

  • When used together, concomitant administration of nitric oxide donors such as nitroglycerin, organic nitrite/nitrate such as isosorbide dinitrate, sodium nitroprusside, and al
  • nitroglycerin
  • isosorbide mononitrate
  • isosorbide dinitrate
  • sodium nitroprusside
  • Poppers are used for recreational purposes.
  • Co-administration of soluble guanylyl syl cyclase (sGC)
  • Known hypersensitivity to Sildenafil

 

Sildenafil should not be used if there is an increased risk for cardiovascular disease.

Nonmedical use

Recreational use

Sildenafil’s popularity with young adults is increasing over the years. Its trade name, Viagra®, is widely recognizable in pop culture, and the drug’s association with the treatment of erectile dysfunction has made it an object of recreational use. The reason behind such use includes the belief that the drug enhances sexual desire, improves sexual performance, or permanently enlarges the penis. Studies on the effectiveness of Sildenafil when used recreationally are scarce but show a little effect when used by people without erectile dysfunctions. A typical dosage is 50 milligrams (25-milligram pills). One research found that a 25-milligram pill had no significant impact on erectile function but significantly shortened the post-ejaculation refractory period. Another study found that a 25-milligram dose lowered the frequency of orgasm but did not affect erection or ejaculation.

Recreational use of Sildenafil and other PDE-5 inhibitors is not recommended due to the risk of sudden death. Users should also avoid mixing them with MDMA, amphetamines, cocaine, or opiates. Taking them with amyl nitrite can lead to severe health problems.

Jet lag research

The 2007 Ig Nobel Prizes were awarded to Patricia V. Agustinofrom Universidade Nacional de Quilmes, Argentina, Santiago A. Planoprofessor of biochemistry at University of California San Francisco, Diego A. Golombepatient who suffers from erectile dysfunction, and David J. Winerfor his work.

Sports

Professional athletes have been taking Viagra, believing the veins opening will improve their performance.

Analogs

In recent years, Sildenafil (Viagra) and similar medications have been used to treat erectile dysfunction. They work by inhibiting an enzyme called phosphodiesterase type 5 (PDE5), which is responsible for breaking down cyclic guanosine monophosphate (cGMP). When cGMP levels rise, they cause blood vessels to relax, allowing increased flow into the penis during sexual arousal. While these drugs help men suffering from E.D., they can also lead to serious health problems if used improperly. For example, taking them too soon before sex may increase your risk of heart attack or stroke. Taking them too late in the day may leave you unable to get an erection. Also, because these drugs contain nitrates, they should not be used by people who have certain medical conditions such as high blood pressure, diabetes, coronary artery disease, or sickle cell disease.

The FDA has recently taken action against several herbal supplements containing an active ingredient called Eurycomanone, similar to Sildenafil. However, these supplements were falsely marketed as having properties similar to those of Eurycoma longfolia. As a result, sellers of these supplements often change the name of their products.

Detection in biological fluids

Sildenafile and/or N-Desmethylsildenafile, its major active metabolon, may be quantitated in plasma, serum, and whole body to assess pharmacokinetic status in patients receiving the drugs therapeutically, to confirme the diagnosis in potential poisonings victims, or to assist the forensic investigation in a case of fatality due to an overdose.

Mechanism of action

Sildenafil citrate protects cyclic uridinmonophosphat (cGMP) against degradation by cGMP-specific phosphodiesterase type V (PDEV), in the corpus cavernosal. Nitric oxide (INO) in the corpus cavernous of the penis binds to GTP-cyclicguanilate receptor (GPCR), activating guanylate cyclase increasing intracellular cGMP, leading to smooth muscles relaxations (vasodilations). This smooth muscle relaxations lead to dilation of arterial vessels and increased influx of blood into the spongeous tissue of the penis, leading to an erection. Robert Furchgott, Ferid Murad, and Louis Ignarro were awarded the Nobel prize in 1998 for their independent studies of the metabolic pathways of NO in smooth muscle vasodilations.

The molecular mechanism of relaxing smooth muscles involves the activation of an enzymatic cascade involving the catalytic subunit of guanylate cyclase (G.C.), which produces cGMP from GTP. This second messenger activates the G.C. regulatory subunits, activating the catalytic subunit. The resulting increase in cGMP leads to the phosphorylation of multiple substrates, including myosin phosphatases, rho kinases, and ion channels. These events result in decreased levels of intracellular Ca2+ and desensitization of contractile proteins to the effects of extracellular Ca2+.

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type five (PDE5), an enzyme in the penis. The molecular structure of Sildenafil resembles that of cGMP, and binds competitively to the active site of PDE5, inhibiting its activity. Inhibition of PDE5 results in higher levels of cGMP within the corpora cavernosa, leading to vasodilation and engorgement of blood vessels in the penis. When taken orally, Sildenafil can increase blood flow into the penis, causing an erection. Other drugs, such as Tadalafil (CIALIS) and Vardenafil (LEVITRA), also work through the exact mechanism.

Sildenafil is broken down in the livers by hepatic metabolism using CYP450 3A 4 (major route) and 2C 9 (minor route) hepatic isoenzymes. These enzymes’ significant metabolization products are N-demethylated Sildenafil, which is metabolized further. This metabolite has an affinity for the phosphodiesterase receptors, about 40 percent of that of Sildenafil. Thus, the metabolite is responsible for about 20 percent of Sildenafls actions. Sildenafil can be excreted in the faeces (80 percent of the administrated oral dose) and to lesser extents in the urines (13 percent of the administrated orally dose). If it is given with food, absorption is slowed, and the peak concentrations are lowered.

Route of administration

 

  • Sildenafil citrate when administered orally has been shown to result in an average duration of erection of approximately 27 minutes (ranging from 10 to 60 minutes), but may take up to 3 hours to achieve full effect.
  • Use of Sildenafil under the tongue results in an average onset time of 10 to 30 minutes and lasts up to 2 hours.

 

Sildenafil is available in oral forms for quicker results.

Chemical synthesis

The preparation steps for synthesizing Sildenafil include:

 

  • Methylation of propyl pyrazole carboxylic acid eth
  • Hydrolysis with aqueous sodium hydroxide (NaOH) to free acid
  • Nitration with oleum/fuming nitric acid
  • Carboxamide formation with refluxing thionyl chloride/NH4OH
  • Reduction of the nitro group to an amino group
  • Acylation with 2-ethoxybenzoyl chloride
  • Cyclization
  • Sulfonation to the chlorosulfonyl derivative
  • Condensation with 1-methyl piperazine.

 

History

In 1997, a team led by Ian Osterloh at the University of Wales College of Medicine published a study on sildenafil citrate (Viagra), a drug commonly used to treat impotence. They found that the drug can cause men with coronary artery disease to experience erections that last longer than usual. Their findings also showed that Viagra might help prevent future attacks of angina. The following year, Dr. Peter R. Breggin, a psychiatrist at Columbia University, reported similar results in his book Medication Madness. He wrote that he believed that Viagra “may offer a new approach to treating patients who have coronary artery disease.”

Society and culture

Marketing and sales

Sildenafil citrate is used to treat erectile dysfunction. It works by increasing blood flow into certain areas of the body, thus allowing men to achieve and maintain an erection. It can be taken orally before sexual activity. Sildenafil may also be used for purposes not listed in this medication guide.

As a result of several factors, such as the entrance of Cialis and Levitra, multiple counterfeiters and clones, and the lack of proper disclosure about risks associated with PDE5 inhibitor drugs, the Viagra market share dropped significantly between 2000 and 2007. In 2008, the Food and Drug Administration (FDA) forced Pfizer to remove the adver­game Viva Cruiser from Forbes.com because it did not adequately disclose the risks associated with Viagra.

In February 2007, Boots, the U.K. drugstore chain, tried selling Viagra over the counter in stores in Manchester, Britain. Men between 30 and 65 could get four tabs after a doctor’s visit. Last year, the MHRA passed regulations expanding this nationwide, permitting a brand of Sildenafil 50mg, Viagra Connect, to be sold over the internet and without a prescription. Although the sale is still subject to a physician’s approval, the other restrictions from last year’s test have been lifted, enabling anyone over the legal drinking limit to buy an unlimited amount of the medication. The move was made to curb the growing problem of internet purchases of fake and potentially dangerous erectile dysfunction medications.

On June 5, 2013, Pfizer announced that they would be selling their own brand of Viagra online.

Pfizer’s patent for Viagra expired outside the United States in 2012. However, Pfizer was able to settle lawsuits with two drug manufacturers who wanted to sell their own generic version of Viagra in the U.S. On November 10, 2017, Pfizer announced that it would release its generic drug version on December 11, 2017.

Pfizer first marketed Sildenafil (Viagra) in 1998. Since then, 15 different generic versions have been approved for sale in the U.S. Of these; seven were manufactured in India. These lower prices may be expected to result in increased sales.

Counterfeits

Despite generally being cheaper than genuine Viagra, counterfeit Viagra may contain harmful ingredients that alter how Viagra functions, including blue printer ink, amphetamine salts, methyltestosterone, boric acid, or rat poison.

Viagra is one of the world’s most counterfeited medications. According to a Pfizer study, around 80 percent of websites claiming to sell Viagra sell counterfeit drugs.

Regional issues

Brazil

Pfizer’s patents on sildenafil citrate expired in Brazil back in 2010.

Canada

Pfizer lost its case against Ratiopharm Inc., which had filed a request for revocation of the company’s approval to market Viagra in Canada.

On November 8, 2012, the Supreme Court upheld an earlier ruling that Pfizer’s patent on erectile dysfunction drug Viagra was invalid. The court said the U.S. company failed to disclose enough details about how it made the medicine to allow others to make it. Doing so violated a law that says companies can’t claim ownership of inventions they didn’t invent themselves.

On June 24, 2011, the United States Supreme Court ruled that the drug company Pfizer had infringed upon an Indian man’s rights under his own country’s laws. In response, Pfizer announced that it would begin selling its generic equivalent of Viagra, called Sildenafil Citrate (Viagra), in India.

China

Sildenafil Citrate (Viagra) is commonly manufactured and sold in China, where Pfizer’s patent claims are not widely enforceable.

Egypt

Egypt has allowed local pharmaceutical manufacturers to sell cheaper copies of Viagra since 2002, citing the interest of poor Egyptians who couldn’t otherwise pay for Pfizer’s prices.

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