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Sildenafil, sold under the brand name Viagra, among others, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmacotherapy) is an imp ...
used to treat erectile dysfunction and pulmonary arterial hypertension. It is unclear if it is effective for treating sexual dysfunction in women. It is taken
by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...
or by
injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
. Onset is typically within twenty minutes and lasts for about two hours. Common side effects include headaches,
heartburn Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the ma ...
, and flushed skin. Caution is advised in those with
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
. Rare but serious side effects include a prolonged erection (priapism) that can lead to damage to the penis, vision problems, and hearing loss. Sildenafil should not be taken by people on
nitrate Nitrate is a polyatomic ion with the chemical formula . Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insolubl ...
s such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure. Sildenafil should not be taken within four hours of taking an
alpha blocker Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , which ...
. Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis. It requires sexual arousal to work. It also results in dilation of the blood vessels in the lungs. Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain. It was approved for medical use in the United States and in the European Union in 1998. In 2020, it was the 183rd most commonly prescribed medication in the United States, with more than 2million prescriptions. It is available as a generic medication. In the United Kingdom, it is available over the counter. Most of the Active Pharmaceutical Ingredient (API) in Sildenafil, Sildenafil citrate, is produced in Pfizer's Ringaskiddy complex, County Cork, which is Pfizer's largest production facility outside of the United States.


Medical uses


Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete
sexual intercourse Sexual intercourse (or coitus or copulation) is a sexual activity typically involving the insertion and thrusting of the penis into the vagina for sexual pleasure or reproduction.Sexual intercourse most commonly means penile–vaginal penetra ...
). 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 Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, heada ...
-induced erectile dysfunction.


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.


Raynaud's phenomenon

Sildenafil and other
PDE5 inhibitor A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supply ...
s are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud's phenomenon; these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes. their role more generally in Raynaud's was not clear.


High-altitude pulmonary edema

Sildenafil has been studied for
high-altitude pulmonary edema High-altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic pulmonary edema that occurs in otherwise healthy people at altitudes typically above . However, cases have also been reported between in more vulnerable subjects. ...
, but its use is currently not recommended for that indication.


Adverse effects

In
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s, the most common
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
of sildenafil use included headache, flushing,
indigestion Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...
, nasal congestion, and impaired vision, including
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
and blurred vision. Some sildenafil users have complained of seeing everything tinted blue (
cyanopsia ''Cyanopsia'' is a medical term for seeing everything tinted with blue. It is also referred to as ''blue vision''. Cyanopsia often occurs for a few days, weeks, or months after removal of a cataract from the eye. Cyanopsia also sometimes occurs as ...
). This cyanopsia can be explained because Sildenafil, while selective for PDE5, does have a minor level of selectivity for PDE6, which is the phosphodiesterase found in the retina. Patients thus taking the drug may experience colorvision abnormalities. Some complained of blurriness and loss of
peripheral vision Peripheral vision, or ''indirect vision'', is vision as it occurs outside the point of fixation, i.e. away from the center of gaze or, when viewed at large angles, in (or out of) the "corner of one's eye". The vast majority of the area in the ...
. In July 2005, the U.S. Food and Drug Administration (FDA) found that sildenafil could lead to vision impairment in rare cases, and a number of studies have linked sildenafil use with non-arteritic 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 Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
, stroke, increased
intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated t ...
, 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 Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...
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 Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...
, both of which can also lead to prolonged plasma half-life levels. The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as
benign prostatic hypertrophy Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...
) 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

Contraindications In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
include: * Concomitant use of nitric oxide donors, organic nitrites and nitrates, such as: ** nitroglycerin **
isosorbide mononitrate Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally ...
**
isosorbide dinitrate Isosorbide dinitrate is a medication used for heart failure, esophageal spasms, and to treat and prevent chest pain from not enough blood flow to the heart. It has been found to be particularly useful in heart failure due to systolic dysfunctio ...
** sodium nitroprusside **
alkyl nitrites In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure , where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds (). The first ...
(commonly known as " poppers") * Concomitant use of soluble guanylyl cyclase stimulators, such as
riociguat Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylate cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) ...
* Known hypersensitivity to sildenafil Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors.


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 sildenafil when used recreationally are limited, but suggest it has little effect when used by those who do not have 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 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...
( 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 it with
amyl nitrite Amyl nitrite is a chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrite functional group. The alkyl group is unreactive and the chemical and biological propertie ...
, another vasodilator, 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 Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. from ...
recovery in
hamster Hamsters are rodents (order Rodentia) belonging to the subfamily Cricetinae, which contains 19 species classified in seven genera.Fox, Sue. 2006. ''Hamsters''. T.F.H. Publications Inc. They have become established as popular small pets. The ...
s.


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 and other synthetic
structural analog A structural analog (analogue in modern traditional English; Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a c ...
s of sildenafil which are
PDE5 inhibitors A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supply ...
have been found as adulterants in a number of "herbal" aphrodisiac products sold over-the-counter. These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles. 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 analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market. The U.S. Food and Drug Administration (FDA) has banned numerous products claiming to be ''
Eurycoma longifolia ''Eurycoma longifolia'' (commonly called ''tongkat ali'', ''pasak bumi'', or ''longjack'') is a flowering plant in the family Simaroubaceae. It is native to Indochina (Cambodia, Laos, Malaysia, Myanmar, Thailand and Vietnam) and Indonesia (the ...
'' 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

Sildenafil protects
cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in ...
(cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum.
Nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ch ...
(NO) in the corpus cavernosum of the penis binds to
guanylate cyclase Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (
vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction ...
) 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 Robert Francis Furchgott (June 4, 1916 – May 19, 2009) was a Nobel Prize-winning American biochemist who contributed to the discovery of nitric oxide as a transient cellular signal in mammalian systems. Early life and education Furchgott ...
,
Ferid Murad Ferid Murad (born September 14, 1936) is an American physician and pharmacologist, and a co-winner of the 1998 Nobel Prize in Physiology or Medicine. Early life Murad was born in Whiting, Indiana. His parents were Henrietta Josephine Bowman o ...
, and
Louis Ignarro Louis J. Ignarro (born May 31, 1941) is an American pharmacologist. For demonstrating the signaling properties of nitric oxide, he was co-recipient of the 1998 Nobel Prize in Physiology or Medicine with Robert F. Furchgott and Ferid Murad. Cu ...
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. The molecular mechanism of smooth muscle relaxation involves the enzyme
CGMP-dependent protein kinase cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle ...
, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase,
RhoA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
, IP3 receptor, phospholipase C, and others. Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation. 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 increased penile response to sexual stimulation. 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 Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half a ...
(Cialis) and
vardenafil Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the brand name Levitra among others. Medical use Vardenafil's indications and contraindications are the same as with other PDE5 inhibitors; it is closel ...
(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 Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...
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: #
Methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate # Hydrolysis with
aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be ...
sodium hydroxide (NaOH) to free
acid In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
# Nitration with
oleum Oleum (Latin ''oleum'', meaning oil), or fuming sulfuric acid, is a term referring to solutions of various compositions of sulfur trioxide in sulfuric acid, or sometimes more specifically to disulfuric acid (also known as pyrosulfuric acid). Oleu ...
/fuming nitric acid #
Carboxamide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it ...
formation with
refluxing Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to reaction ...
thionyl chloride/NH4OH # Reduction of
nitro group In organic chemistry, nitro compounds are organic compounds that contain one or more nitro functional groups (). The nitro group is one of the most common explosophores (functional group that makes a compound explosive) used globally. The nit ...
to
amino group In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
#
Acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with s ...
with 2-ethoxybenzoyl chloride #
Cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
# Sulfonation to the chlorosulfonyl derivative #
Condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor to ...
with 1-methylpiperazine.


History

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's
Sandwich, Kent Sandwich is a town and civil parish in the Dover District of Kent, south-east England. It lies on the River Stour and has a population of 4,985. Sandwich was one of the Cinque Ports and still has many original medieval buildings, including ...
, research facility in England. It was initially studied for use in hypertension (high blood pressure) and
angina pectoris Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of obstru ...
(a symptom of
ischaemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
). The first clinical trials were conducted in
Morriston Hospital Morriston Hospital ( cy, Ysbyty Treforys) is a 750-bed hospital located in Cwmrhydyceirw near Morriston in Swansea, Wales. It is managed by Swansea Bay University Health Board. Alongside its role as a district general hospital, Morriston is a t ...
in Swansea. Phase I
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s 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; this decision became an often-cited example of
drug repositioning Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes. Repurposing achievements A number of successes have been achieved, the foremost including sildenafil (Viagra) for erect ...
. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 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 billion.


Society and culture


Marketing and sales

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 Robert Joseph Dole (July 22, 1923 – December 5, 2021) was an American politician and attorney who represented Kansas in the United States Senate from 1969 to 1996. He was the Republican Leader of the Senate during the final 11 years of his t ...
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 that many fake
aphrodisiac An aphrodisiac is a substance that increases sexual desire, sexual attraction, sexual pleasure, or sexual behavior. Substances range from a variety of plants, spices, foods, and synthetic chemicals. Natural aphrodisiacs like cannabis or cocain ...
s 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 2008, the FDA forced Pfizer to remove ''Viva Cruiser'', an advergame for Viagra, from appearing on Forbes.com, after the game failed to disclose risk information about the drug. In February 2007, it was announced that
Boots A boot is a type of footwear. Boot or Boots may also refer to: Businesses * Boot Inn, Chester, Cheshire, England * Boots (company), a high-street pharmacy chain and manufacturer of pharmaceuticals in the United Kingdom * The Boot, Cromer Str ...
, the UK pharmacy chain, would try
over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
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. In 2017, the
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptably ...
(MHRA) enacted legislation that expanded this nationwide, allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills. 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 people 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. In December 2017, Pfizer released its own generic version of Viagra. , the U.S. Food and Drug Administration has approved fifteen 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.


Counterfeits

Counterfeit Viagra, despite generally being cheaper, can contain harmful substances or substances that affect how Viagra works, such as blue printer ink,
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
s,
metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is ...
,
boric acid Boric acid, more specifically orthoboric acid, is a compound of boron, oxygen, and hydrogen with formula . It may also be called hydrogen borate or boracic acid. It is usually encountered as colorless crystals or a white powder, that dissolves ...
, and rat poison. Viagra is one of the world's most counterfeited medicines. According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.


Regional issues


Brazil

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


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 Ratiopharm is a German pharmaceutical company that is Europe's leading generics brand. Ratiopharm was owned by Adolf Merckle and makes generic pharmaceuticals. They are based in Ulm, Germany, with products being distributed in over 35 countries ...
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. To remain competitive, Pfizer then reduced the price of Viagra in Canada. However, on 9 November 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 22 April 2013, the Supreme Court of Canada invalidated Pfizer's patent altogether.


China

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


Egypt

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.


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 inhibitor A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supply ...
s (see below) as treatment of impotence was invalidated in 2000 because of
obviousness The inventive step and non-obviousness reflect a general patentability requirement present in most patent laws, according to which an invention should be sufficiently inventive—i.e., non-obvious—in order to be patented. In other words, " henon ...
; this decision was upheld on appeal in 2002.


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 Cipla Limited (stylized as Cipla) is an Indian multinational pharmaceutical company, headquartered in Mumbai. Cipla primarily develops medicines to treat respiratory disease, cardiovascular disease, arthritis, diabetes, depression and many oth ...
), Edegra (
Sun Pharmaceutical Sun Pharmaceutical Industries Limited (d/b/a Sun Pharma) is an Indian multinational pharmaceutical company headquartered in Mumbai, that manufactures and sells pharmaceutical formulations and active pharmaceutical ingredients (APIs) in more ...
), Penegra (
Zydus Cadila Zydus Lifesciences Limited, formerly known as Cadila Healthcare Limited, is an Indian multinational pharmaceutical company headquartered in Ahmedabad, which is primarily engaged in the manufacture of generic drugs. It ranked 100th in the Fortu ...
), Manly (Cooper Pharma) and Zenegra ( Alkem Laboratories).


New Zealand

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.


South Korea

In 1999 South Korea granted two patents to Pfizer related to sildenafil. The first document guaranteed sole production and sale of the substance until 2012, while the second gave Pfizer the exclusive use to treating erectile dysfunction with sildenafil until 2014. In 2011
Hanmi Pharmaceutical Hanmi Pharmaceutical () is a South Korean pharmaceutical company that is headquartered in Seoul. History 1973 to 2009 Hanmi was founded in 1973 by Lim Sung-ki, who was a pharmacist. It was originally named Lim, Sung-ki Pharmaceutical Co., but ...
and
CJ CheilJedang CJ CheilJedang is a South Korean food company based in Seoul that manufactures food ingredients, ambient, frozen and chilled packaged food products, pharmaceuticals and biotechnology. Its brands include bibigo, Gourmet and Hatbahn. bibigo brand ...
launched a suit against the exclusive use patent. The Korean Court system made a ruling against Pfizer in June 2012, allowing for the unhindered domestic production of generic prescription sildenafil. During 2012 Viagra lost its position as the top selling erectile dysfunction treatment in South Korea. This development was credited largely "due to the introduction of generic products." Generic sildenafil became publicly available in May. Sales of PalPal by Hanmi Pharmaceuticals totalled ₩22 billion or about 86% the market share of Viagra that year. By 2017 there were over 50 generic sildenafil pills available. During that year Viagra sales slumped to 38% that of Palpal.


United Kingdom

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.


United States

Sildenafil is available as a generic drug in the United States, labeled for pulmonary arterial hypertension. branded pills cost about 50 times more than generic ones. In the United States the branded 50 mg pill cost is between 25.17 and US$37.88. 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. This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. 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. Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills. In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. This would be marketed as Viagra. 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. An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.


References


External links

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'' (University of Nottingham) {{cite journal , vauthors=Kayık G, Tüzün NŞ, Durdagi S , title=In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors , journal= Journal of Biomolecular Structure & Dynamics , volume=35 , issue=13 , pages=2830–2852 , date=October 2017 , pmid=27581752 , doi=10.1080/07391102.2016.1231634 , s2cid=21682809 , url= , issn= Erectile dysfunction drugs Lactams HERG blocker PDE5 inhibitors Pfizer brands Phenol ethers Piperazines Products introduced in 1998 Pyrazolopyrimidines Wikipedia medicine articles ready to translate