Sildenafil , sold as a brand name Viagra among others, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Its effectiveness to treat sexual dysfunction in women has not been proven.
Common side effects include headache and heartburn, and skin reddening. Caution is advised in those with cardiovascular disease. Rare but serious side effects include prolonged erections, which can cause damage to the penis, and sudden hearing loss. Sildenafil should not be taken by people taking nitrates such as nitroglycerin (glycerine trinitrate), as this can cause severe and potentially fatal blood pressure drops.
Sildenafil acts by inhibiting phosphodiesterase type 5 cGMP (phosphodiesterase 5, PDE 5 ), an enzyme that promotes cGMP degradation, which regulates blood flow in the penis.
Pfizer scientist Andrew Bell, David Brown, and Nicholas Terrett initially found sildenafil as a treatment for various cardiovascular disorders. Since becoming available in 1998, sildenafil has become a common treatment for erectile dysfunction; Its main competitors are tadalafil (trade name Cialis) and vardenafil (Levitra).
Video Sildenafil
Medical use
Sex Sexual dysfunction
The main indication of sildenafil is the treatment of erectile dysfunction (inability to maintain a satisfactory erection to resolve sexual intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.
Sexual dysfunction associated with antidepressants
Temporary evidence suggests that sildenafil may help men with erectile dysfunction induced by antidepressants.
Pulmonary hypertension
While sildenafil increases some disease markers in people with pulmonary arterial hypertension, sildenafil does not appear to affect the risk of death or serious side effects in 2014.
Raynaud's phenomenon
Sildenafil and other PDE5 inhibitors are used off-label to reduce vasospasm and treat severe ischemia and ulcers on the fingers and toes for people with secondary Raynaud's phenomenon; this drug has moderate efficacy to reduce the frequency and duration of vasospastic episodes. By 2016, their role is more common in Raynaud is not clear.
Maps Sildenafil
Adverse effects
In clinical trials, the most common adverse effects of sildenafil use include headache, redness, indigestion, nasal congestion, and visual impairment, including photophobia and blurred vision. Some users of sildenafil complain of seeing all blue (cyanopsia). Some complain of blurriness and loss of peripheral vision. In July 2005, the FDA found that sildenafil may cause visual impairment in rare cases and a number of studies have linked the use of sildenafil with anterior non-arteritic ischemic optic neuropathy.
The rare and serious side effects found through post-marketing surveillance include prolonged erections, severe low blood pressure, myocardial infarction (heart attack), ventricular arrhythmia, stroke, increased intraocular pressure, and sudden hearing loss. In October 2007, the FDA announced that labeling for all PDE5 inhibitors, including sildenafil, required more prominent warnings about the potential risk of sudden hearing loss.
Interactions
Treatment should be performed by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit sildenafil metabolism, effectively multiplying plasma levels of sildenafil, increasing the incidence and severity of side effects. Those who use protease inhibitors are recommended to limit their sildenafil use to no more than one dose of 25mg every 48 hours. Other drugs that interfere with sildenafil metabolism include erythromycin and cimetidine, both of which can also cause a prolonged half-life of the plasma beak.
Use of sildenafil and blocker? 1 (usually prescribed for hypertension or for urological conditions, such as benign prostatic hypertrophy) at the same time can cause low blood pressure, but this effect does not occur if they are taken at least 4 hours.
Contraindications
Contraindications include:
- Concurrent use of donor nitric oxide, organic nitrites and nitrates, such as:
- nitroglycerin
- isosorbide mononitrat
- isosorbide dinitrate
- sodium nitroprusside
- alkyl nitrite (commonly known as "poppers")
- Common use of a soluble guanylyl cyclase stimulator, such as riociguat
- Known hypersensitivity to sildenafil
Sildenafil should not be used if sexual activity is not recommended because of underlying cardiovascular risk factors (such as recent cardiac surgery, stroke or heart attack, etc.).
Nonmedical use
Use of recreation
The popularity of Sildenafil with young adults has increased over the years. The trade names Sildenafil, Viagra, are widely recognized in popular culture, and drug associations by treating erectile dysfunction have led to the use of recreation. The reasons behind such use include the belief that drugs increase libido, improve sexual performance, or permanently increase penis size. Studies on the effects of Viagra when used in recreation are limited, but suggest it has little effect when used by those who do not suffer from erectile dysfunction. In one study, a dose of 25 mg proved not to cause significant changes in erectile quality, but reduced postoperative refractory time. The study also noted a significant placebo effect in the control group.
The use of recreational sildenafil and other unregistered PDE5 inhibitors was noted to be very high among drug users. Sildenafil is sometimes used to counteract the effects of other substances, often forbidden. Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effects of erectile dysfunction, a combination known as "sextasy", "rockin 'and rollin'" or "mixed trace". Mixing with amyl nitrite is very dangerous and potentially fatal.
Research Jet lag
The 2007 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 improve their appearance.
Analog
Acetildenafil and other synthetic structural analogues of sildenafil which are PDE5 inhibitors have been found to be adul- merate in a number of over-the-counter "herbal" aphrodisiac products. This analogy has not undergone rigorous testing that drugs such as sildenafil have passed, and thus have an unknown side effect profile. Several attempts have been made to ban these drugs, but so far progress has been slowed, because, even in jurisdictions that have laws targeting designer drugs, the law is designed to ban analog drug abuse rather than drug analogs prescription. However, at least one court case has resulted in a product being taken from the market.
The US FDA has banned many products that claim to be Eurycoma longifolia which, in fact, contains only sildenafil analogues. Such fake herbal sellers usually respond by simply changing the name of their product.
Detection in biological fluid
Sildenafil and/or N-desmethylsildenafil, its main active metabolite, can be quantified in plasma, serum, or whole blood to assess pharmacokinetic status in those who receive the drug therapeutically, to confirm the diagnosis of potential toxicity victims, or to assist in forensics. investigation in case of a fatal overdose.
Action mechanism
Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the cavernosum corpus of the penis binds to the guanylate cyclase receptors, which results in elevated cGMP levels, leading to smooth muscle relaxation (vasodilation) of the helicine artery intima pillow. Relaxation of this smooth muscle causes vasodilation and increased blood flow to the penile sponge tissue, 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 the specific phosphodiesterase type cGMP 5 (PDE5), which is responsible for cGMP degradation in the corpus cavernosum. The molecular structure of sildenafil is similar to 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 due to lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate with the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).
Sildenafil is broken down by liver metabolism using cytochrome p450 enzymes, especially CYP450 3A4 (main route), but also by CYP2C9 (minor route) liver isoenzymes. The main product of metabolisation by these enzymes is sildenafil N-desmethylated, which is further metabolized. This metabolite also has an affinity for PDE receptors, about 40% of sildenafil. Thus, the metabolite is responsible for about 20% of the sildenafil action. Sildenafil is excreted as a metabolite especially in the feces (about 80% of the given oral dose) and to a lesser degree in urine (about 13% of the given oral dose). If taken with a high-fat diet, absorption is reduced; the time required to achieve maximum plasma concentration increases by about an hour, and the maximum concentration itself decreases by almost a third.
Administrative route
- When taken by mouth sildenafil for erectile dysfunction results in an average time to start erection 27 minutes (ranging from 12 to 70 minutes).
- Under the tongue the use of sildenafil for erectile dysfunction results on average onset of action 15 minutes and lasts for an average of 40 minutes.
There is also a sildenafil mouth spray preparation for faster onset of action.
Chemical synthesis
The preparation steps for sildenafil synthesis are:
- Methylation of 3-propylpyrazole-5-carboxylic ethyl ester with dimethyl sulfate heat
- Hydrolysis with dilute sodium hydroxide (NaOH) to liberate acid
- Nitration with oleum/fuming nitric acid
- Carboxamide formation with thionyl chloride reflux/NH 4 OH
- Reduction of nitro groups into amino groups
- Acylation with 2-ethoxybenzoyl chloride
- Cyclization
- Sulfonation to chlorosulfonyl derivatives
- Condensation with 1-methylpiperazine.
History
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent, a research facility in England. Initially studied for use in hypertension (high blood pressure) and angina pectoris (symptoms of ischemic heart disease). The first clinical trial was conducted at Morriston Hospital in Swansea. Phase I clinical trials under Ian Osterloh suggest the drug has little effect on angina, but it can induce marked penile erection. Pfizer therefore decided to market it for erectile dysfunction, not for angina; This decision becomes a frequently cited example of drug repositioning. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on March 27, 1998, becoming the first approved oral treatment to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. This soon became a huge success: Viagra's annual sales peaked in 2008 at US $ 1.934 billion.
The British press describes Peter Dunn and Albert Wood as the inventors of the drug, but only Andrew Bell, David Brown, and Nicholas Terrett are listed in the original composition of material patents.
Society and culture
Marketing and sales
In the US even though sildenafil is only available with a prescription from a doctor, it is advertised directly to consumers on TV (famously supported by former US Senator Bob Dole and soccer star PelÃÆ'Â ©). Many sites on the Internet offer Viagra for sale after "online consultation", often a simple web questionnaire. The name Viagra has become so famous, many fake aphrodisiacs now call themselves "herbal viagra" or presented as blue tablets mimicking the shape and color of Pfizer's products. Viagra is also informally known as "vitamin V", "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 2007, Viagra's global share has fallen to around 50% due to several factors, including the inclusion of Cialis and Levitra, along with some forgery and clones, and vision loss reports on people taking PDE5 inhibitors.
In February 2007, it was announced that Boots, the UK pharmaceutical chain, would be trying to sell freely sold Viagra in stores in Manchester, England. Men between the ages of 30 and 65 will be eligible to buy four tablets after consultation with pharmacists. By 2017, Medicines and Health Products Regulatory Agency enacts this nationally expanded law, enabling Sildenafil branded special formulations, Viagra Connect (50mg) , for sale on the counter and without prescription throughout the UK from early 2018. While sales remain subject to consultation with pharmacists, other restrictions of the trial have been removed, allowing customers over the age of 18 to purchase unlimited pills. The decision was made, in part, to reduce online sales of erectile dysfunction treatments that are potentially dangerous and dangerous.
On May 6, 2013, Pfizer, which produces Viagra, told the Associated Press that they will start selling drugs directly to patients on its website.
Patent Pfizer in Viagra ends outside the US in 2012; in the US they are set to expire, but Pfizer resolves litigation with respectively Mylan and Teva who agree that both companies can introduce generic drugs in the US on December 11, 2017. In December 2017, Pfizer released its own generic version of Viagra.
Counterfeit
Fake Viagra, though generally cheaper, may contain harmful substances or substances that affect the way Viagra works, such as blue printer ink, amphetamine, metronidazole, boric acid, and rat poison.
Viagra is one of the most fake drugs in the world. According to a Pfizer study, about 80% of sites claiming to sell Viagra sell counterfeit goods.
Regional issues
European Union
The Pfizer patent on sildenafil citrate ends in several EU member states, Austria, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, Sweden, England and Switzerland on June 21, 2013. The British patent held by Pfizer on the use of PDE5 inhibitors (see below) as impotence treatment became invalid in 2000 as it was clear; this decision was upheld in appeal in 2002.
United Kingdom
There are 2,958,199 recipes for Sildenafil in 2016 in the UK, compared to 1,042,431 in 2006.
In 2018, Viagra Connect, a special Sildenafil formulation marketed by Pfizer, becomes available for sale without a prescription in the UK, in an effort to expand availability and reduce demand for counterfeit products.
United States
Sildenafil is available as a generic drug in the United States, which is labeled for pulmonary arterial hypertension. In 2016 branded pills cost about 50 times more than the generic ones. In the United States by 2015, the cost of branded 50 mg pills is between 25.17 and 37.88 USD.
In the United States, Pfizer receives two patents for sildenafil: one for indications for treating cardiovascular disease (marketed as Revatio) and another for indications to treat erectile dysfunction (marketed as Viagra). This substance is the same under both trade names.
In 1992, Pfizer filed a patent covering the substance of sildenafil and its use to treat cardiovascular disease. It will be marketed as Revatio. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) ends at the end of 2012. The generic version of this low-dose sildenafil form is already available in the US from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013. Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dose as the Viagra brand, so using the usual dose required to treat ED requires the patient to take some pills.
In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. It will be marketed as Viagra. This patent was issued in 2002 and will expire in 2019. Teva sued for the last patent to be canceled, but Pfizer wins in federal district court in August 2011. The deal with Pfizer allows Teva to begin providing generic drugs in December 2017.
Canada
In Canada, Pfizer patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by Federal Court in June 2010, on application by Ratiopharm Inc.
On November 8, 2012, the Supreme Court of Canada ruled that the Pfizer 2,163,446 patent on Viagra was invalid from the start because the company did not provide full disclosure in its application. His decision, Teva Canada Ltd. v. Pfizer Canada Inc. , refers to section 27 (3) (b) of the Patent Act which requires that disclosure should include sufficient information "to enable any person skilled in the art or science related to" to produce it. He added further: "As a matter of policy and strong legal interpretation, patented parties can not be allowed to 'play' the system in this way, this, I think, is the main problem in this appeal."
Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada issued its decision. To stay competitive, Pfizer then reduces the price of Viagra in Canada. However, on November 9, 2012, Pfizer filed a motion for a re-appeal in the Supreme Court of Canada, arguing that the court inadvertently exceeded its jurisdiction by canceling the patent. Finally, on April 22, 2013, the Supreme Court of Canada denies Pfizer's overall patent.
India
The production and sale of sildenafil citrate drugs known as "Generic Viagra" is common in India, where Pfizer patent claims do not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).
China
Manufacture and sale of common sildenafil citrate drugs in China, where Pfizer's patent claims are not widely applicable.
New Zealand
Sildenafil has been reclassified in New Zealand in 2014 so it can be purchased on the table from a pharmacist. It is estimated that this reduces sales over the Internet and is safer because men can be referred for medical advice if appropriate.
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 the poor who would not be able to afford Pfizer's price.
The Pfizer patent on sildenafil citrate ends in Brazil in 2010.
References
External links
- Viagra Official Website
- Official Revatio Site
- prescribes information for Viagra and prescribes information for Revatio from Pfizer
- FDA Information
- MedlinePLUS information, including side effects
- US. National Medical Library: Drug Information Portal - Sildenafil
- Viagra on Periodic Video Table (University of Nottingham)
Source of the article : Wikipedia
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