Sildenafil
Encyclopedia
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug
used to treat erectile dysfunction
and pulmonary arterial hypertension
(PAH). It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company
Pfizer
. It acts by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme
that delays degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil
(Cialis) and vardenafil
(Levitra).
(inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes
.
People on antidepressant
s may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation. Following up to earlier reports from 1999, the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.
pulmonary arterial hypertension
(PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle
of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20-milligram tablets are white and round. Sildenafil joins bosentan
and prostacyclin
-based therapies for this condition.
such as that suffered by mountain climbers. While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.
Viagra pills are blue and diamond-shaped with the word "Pfizer" engraved on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) engraved on the other. The dose of sildenafil for erectile dysfunction is 25 mg to 100 mg taken not more than once per day between 30 minutes and 4 hours prior to sexual intercourse
.
The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.
s, the most common adverse effect
s of sildenafil use included headache
, flushing
, dyspepsia
, nasal congestion
and impaired vision, including photophobia
and blurred vision.
Some sildenafil users have complained of seeing everything tinted blue (cyanopsia
). Some complained of blurriness and loss of peripheral vision
. In July 2005, the U.S.
Food and Drug Administration
found that sildenafil could lead to vision impairment in rare cases and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy
.
Rare but serious adverse effects found through postmarketing surveillance
include priapism
, severe hypotension
, myocardial infarction
(heart attack), ventricular arrhythmia
s, stroke
, increased intraocular pressure
, and sudden hearing loss
. As a result of these postmarketing reports, in October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.
for the treatment of HIV
. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25 mg dose every 48 hours.
Concomitant use of sildenafil and an alpha blocker
may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.
. This study also noted a significant placebo effect
in the control group.
Unprescribed recreational use of sildenafil and other PDE-5 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
(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 with amyl nitrite
is particularly dangerous and potentially fatal.
in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina for their discovery that Viagra aids jet lag
recovery in hamsters. Their research was published in the Proceedings of the National Academy of Sciences
.
is a structural analog of sildenafil, one of the PDE5 inhibitors found in a number of "herbal" aphrodisiac products sold over-the-counter. This class of analogs has not undergone any of the rigorous testing that drugs like sildenafil have passed, and, thus, has an unknown side-effect profile. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.
The United States FDA has banned numerous products claiming to be Eurycoma longifolia
that, in fact, contain only analogs of sildenafil. Peddlers of such fake herbals typically respond by just changing the names of their products.
(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 metabolised
by liver
enzyme
s and excreted by both the liver and kidney
s. 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.
, 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
. Phase I clinical trial
s under the direction of Ian Osterloh
suggested that the drug had little effect on angina, but that it could induce marked penile erection
s. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patent
ed in 1996, approved for use in erectile dysfunction by the United States Food and Drug Administration
on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.
The British Press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes. Their names are on the manufacturing patent application, but the original patent on the synthesis of the the drug was filed by Nicholas Terrett and Peter Ellis.
Bob Dole
and soccer
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
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", "Blue Diamond" as well as various other nicknames.
In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction
pills. By 2007, Viagra's global share had plunged to about 50 percent 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 February 2007, it was announced that Boots
, the UK pharmacy chain, would try over-the-counter
sales of Viagra in stores in Manchester
, England
. Men between the ages 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist
.
patent held by Pfizer on the use of PDE5 inhibitor
s (see below) as treatment of impotence was invalidated in 2000 because of obviousness
; this decision was upheld on appeal in 2002. But there are two other patents covering the methods for manufacturing Viagra, and Pfizer has maintained its monopoly on the drug in the UK.
Pfizer's patent on sildenafil citrate expired in Brazil in 2010. It was originally believed that Pfizer's patents would expire in the United States in March 2012., but an August 2011 federal district court case raises the prospect that at least one of Pfizer's patents will be valid until 2019.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used to treat erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and pulmonary arterial hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(PAH). It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. It acts by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that delays degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil
Tadalafil
Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
(Cialis) and vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
(Levitra).
Sexual dysfunction
The primary indication of sildenafil is treatment of erectile dysfunctionErectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
(inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
People on antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation. Following up to earlier reports from 1999, the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.
Pulmonary hypertension
As well as erectile dysfunction, sildenafil citrate is also effective in the rare diseaseRare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
pulmonary arterial hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle
Ventricle (heart)
In the heart, a ventricle is one of two large chambers that collect and expel blood received from an atrium towards the peripheral beds within the body and lungs. The Atria primes the Pump...
of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20-milligram tablets are white and round. Sildenafil joins bosentan
Bosentan
Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary artery hypertension . It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer.-Mechanism of action:Bosentan is...
and prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
-based therapies for this condition.
Altitude sickness
Sildenafil has been shown to be useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sicknessAltitude sickness
Altitude sickness—also known as acute mountain sickness , altitude illness, hypobaropathy, or soroche—is a pathological effect of high altitude on humans, caused by acute exposure to low partial pressure of oxygen at high altitude...
such as that suffered by mountain climbers. While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason.
Dosage
Sexual intercourse
Sexual intercourse, also known as copulation or coitus, commonly refers to the act in which a male's penis enters a female's vagina for the purposes of sexual pleasure or reproduction. The entities may be of opposite sexes, or they may be hermaphroditic, as is the case with snails...
.
The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day. Revatio pills are white, round, film-coated tablets imprinted with "RVT 20" embossed on one side.
Adverse effects
In clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, the most common adverse effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s of sildenafil use included headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, nasal congestion
Nasal congestion
Nasal congestion is the blockage of the nasal passages usually due to membranes lining the nose becoming swollen from inflamed blood vessels. It is also known as nasal blockage, nasal obstruction, blocked nose, stuffy nose, or stuffed up nose.Nasal congestion has many causes and can range from a...
and impaired vision, including photophobia
Photophobia
Photophobia is a 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 actual physical photosensitivity of the eyes, though the term...
and blurred vision.
Some sildenafil users have complained of seeing everything tinted blue (cyanopsia
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 a side effect of taking sildenafil , Cialis, or Levitra...
). Some complained of blurriness and loss of peripheral vision
Peripheral vision
Peripheral vision is a part of vision that occurs outside the very center of gaze. There is a broad set of non-central points in the field of view that is included in the notion of peripheral vision...
. In July 2005, the U.S.
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
found that sildenafil could lead to vision impairment in rare cases and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy
Anterior ischemic optic neuropathy
Anterior ischemic optic neuropathy is a medical condition involving loss of vision due to damage to the optic nerve from insufficient blood supply. AION is generally divided into two types: arteritic AION and non-arteritic AION...
.
Rare but serious adverse effects found through postmarketing surveillance
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...
include priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, severe hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(heart attack), ventricular arrhythmia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
s, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, increased intraocular pressure
Intraocular pressure
Intraocular pressure 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 from glaucoma...
, and sudden hearing loss
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
. As a result of these postmarketing reports, in October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.
Interactions
Care should be exercised by patients that are also taking protease inhibitorsProtease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
for the treatment of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25 mg dose every 48 hours.
Concomitant use of sildenafil and an alpha blocker
Alpha blocker
Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...
may lead to low blood pressure, but this effect does not occur if they are taken at least four hours apart.
Contraindications
Contraindications include:- When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprussideSodium nitroprussideSodium nitroprusside is the inorganic compound with the formula Na2[Fe5NO]·2H2O. This red-coloured salt, which is often abbreviated SNP, is a potent vasodilator...
, amyl nitriteAmyl nitriteAmyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
("poppersPoppersPoppers is a slang term for various alkyl nitrites inhaled for recreational purposes, particularly isopropyl nitrite and isobutyl nitrite , and now more rarely, butyl nitrite and amyl nitrite...
") - In men for whom sexual intercourseSexual intercourseSexual intercourse, also known as copulation or coitus, commonly refers to the act in which a male's penis enters a female's vagina for the purposes of sexual pleasure or reproduction. The entities may be of opposite sexes, or they may be hermaphroditic, as is the case with snails...
is inadvisable due to cardiovascular risk factors - Severe hepatic impairmentChronic liver diseaseChronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis.- Causes :...
(decreased liver function) - Severe impairment in renal functionRenal functionRenal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
- HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(low blood pressure) - Recent strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or heart attackMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die... - Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterasePhosphodiesteraseA phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
s)
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 viagra when used recreationally are limited, but suggest that it has little effect when used by those not suffering from erectile dysfunction. In one study, a 25 mg dose was shown to cause no significant change in erectile quality, but did reduce the post-ejaculatory refractory timeRefractory period (sex)
In sexuality, the refractory period is the recovery phase after orgasm during which it is physiologically impossible for an individual to have additional orgasms. Most men are unable to maintain or achieve an erection during this time, and many perceive a psychological feeling of "satiation" and...
. This study also noted a significant placebo effect
Placebo effect
Placebo effect may refer to:* Placebo effect, the tendency of any medication or treatment, even an inert or ineffective one, to exhibit results simply because the recipient believes that it will work...
in the control group.
Unprescribed recreational use of sildenafil and other PDE-5 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
Methylenedioxymethamphetamine
MDMA is an entactogenic drug of the phenethylamine and amphetamine class of drugs. In popular culture, MDMA has become widely known as "ecstasy" , usually referring to its street pill form, although this term may also include the presence of possible adulterants...
(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 with amyl nitrite
Amyl nitrite
Amyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
is particularly dangerous and potentially fatal.
Jet lag research
The 2007 Ig Nobel PrizeIg Nobel Prize
The Ig Nobel Prizes are an American parody of the Nobel Prizes and are given each year in early October for ten unusual or trivial achievements in scientific research. The stated aim of the prizes is to "first make people laugh, and then make them think"...
in Aviation went to Patricia V. Agostino, Santiago A. Plano, and Diego A. Golombek of Universidad Nacional de Quilmes, Argentina for their discovery that Viagra aids jet lag
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...
recovery in hamsters. Their research was published in the Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
The Proceedings of the National Academy of Sciences of the United States of America, usually referred to as PNAS, is the official journal of the United States National Academy of Sciences...
.
Use in sports
Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe that it will enhance their performance.Analogs
AcetildenafilAcetildenafil
Acetildenafil is a drug which acts as a phosphodiesterase inhibitor. It is a structural analogue of sildenafil which has been detected in numerous different brands of supposedly "herbal" aphrodisiac products sold to boost libido and alleviate erectile dysfunction.A range of designer analogues of...
is a structural analog of sildenafil, one of the PDE5 inhibitors found in a number of "herbal" aphrodisiac products sold over-the-counter. This class of analogs has not undergone any of the rigorous testing that drugs like sildenafil have passed, and, thus, has an unknown side-effect profile. Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However, at least one court case has resulted in a product being taken off the market.
The United States FDA has banned numerous products claiming to be Eurycoma longifolia
Eurycoma longifolia
Eurycoma longifolia is a flowering plant in the family Simaroubaceae, native to Indonesia, Malaysia, and, to a lesser extent, Thailand, Vietnam, and Laos...
that, in fact, contain only analogs of sildenafil. Peddlers of such fake herbals typically respond by just changing the names of their products.
Detection in biological fluids
Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantitated in plasma, serum or whole blood in order to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.Mechanism of action
The mechanism of action of sildenafil involves the protection of cyclic guanosine monophosphateCyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
(cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum
Corpus cavernosum penis
The corpus cavernosum penis is one of a pair of sponge-like regions of erectile tissue which contain most of the blood in the penis during penile erection...
. Nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO) in the corpus cavernosum of the penis binds to guanylate cyclase
Guanylate cyclase
-Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:...
receptors, which results in increased levels of cGMP, leading to smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
relaxation (vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
) of the intimal cushions of the helicine arteries
Helicine arteries of penis
The helicine arteries of penis are arteries in the penis. They are found in the corpora cavernosa penis.They are involved in the process of erection.-Anatomy:...
. 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 F. Furchgott
Robert Francis Furchgott was a Nobel Prize-winning American biochemist.Furchgott was born in Charleston, SC, to Arthur Furchgott and Pena Sorentrue Furchgott...
, Ferid Murad
Ferid Murad
Ferid Murad is an Albanian-American physician and pharmacologist, and a co-winner of the 1998 Nobel Prize in Physiology or Medicine. He is also an honorary member of the Academy of Sciences and Arts of Kosovo.- Life :...
and Louis Ignarro
Louis Ignarro
Louis J. Ignarro is an American pharmacologist. He was corecipient of the 1998 Nobel Prize in Physiology or Medicine with Robert F...
won the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
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
Corpus cavernosum penis
The corpus cavernosum penis is one of a pair of sponge-like regions of erectile tissue which contain most of the blood in the penis during penile erection...
. 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
Tadalafil
Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
(Cialis) and vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
(Levitra).
Sildenafil is metabolised
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
by liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s and excreted by both the liver and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. 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.
Chemical synthesis
The preparation steps for synthesis of sildenafil are as follows:- MethylationMethylationIn the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate - HydrolysisHydrolysisHydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
with aqueous NaOH to free acid - NitrationNitrationNitration is a general chemical process for the introduction of a nitro group into a chemical compound. The dominant application of nitration is for the production of nitrobenzene, the precursor to methylene diphenyl diisocyanate...
with oleum/fuming nitric acid - CarboxamideCarboxamideIn organic chemistry carboxamides are functional groups with the general structure R-CO-NH2 with R as an organic substituent.Two amino acids, asparagine and glutamine, have a carboxamide group in them....
formation with refluxing thionyl chloride/NH4OH - ReductionRedoxRedox reactions describe all chemical reactions in which atoms have their oxidation state changed....
of nitro group to amino - AcylationAcylationIn chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
with 2-ethoxybenzoyl chloride - Cyclization
- Sulfonation to the chlorosulfonyl derivative
- CondensationCondensationCondensation is the change of the physical state of matter from gaseous phase into liquid phase, and is the reverse of vaporization. When the transition happens from the gaseous phase into the solid phase directly, the change is called deposition....
with 1-methylpiperazine.
Origins
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, KentSandwich, Kent
Sandwich is a historic town and civil parish on the River Stour in the Non-metropolitan district of Dover, within the ceremonial county of Kent, south-east England. It has a population of 6,800....
, research facility in England. It was initially studied for use in hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(high blood pressure) and angina pectoris (a symptom of ischaemic heart disease
Ischaemic heart disease
Ischaemic or ischemic heart disease , or myocardial ischaemia, is a disease characterized by ischaemia of the heart muscle, usually due to coronary artery disease...
). The first clinical trials were conducted in Morriston Hospital
Morriston Hospital
Morriston Hospital is a 750 bed hospital located in Cwmrhydyceirw near Morriston in Swansea, Wales. Morriston is the largest hospital in the city and county of Swansea and is operated by Abertawe Bro Morgannwg University Health Board. Alongside its role as a district general hospital, Morriston...
in Swansea
Swansea
Swansea is a coastal city and county in Wales. Swansea is in the historic county boundaries of Glamorgan. Situated on the sandy South West Wales coast, the county area includes the Gower Peninsula and the Lliw uplands...
. Phase I clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s under the direction of Ian Osterloh
Ian Osterloh
Ian Osterloh is a clinical researcher for Pfizer, Inc. who led the development of sildenafil citrate , as well as a number of Pfizer medications for cardiovascular disease.-References:...
suggested that the drug had little effect on angina, but that it could induce marked penile erection
Erection
Penile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
s. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
ed in 1996, approved for use in erectile dysfunction by the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra peaked in 2008 at US$1,934 million.
The British Press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim that Pfizer disputes. Their names are on the manufacturing patent application, but the original patent on the synthesis of the the drug was filed by Nicholas Terrett and Peter Ellis.
Marketing and sales
Even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on U.S. TV (famously being endorsed by former United States SenatorUnited States Senate
The United States Senate is the upper house of the bicameral legislature of the United States, and together with the United States House of Representatives comprises the United States Congress. The composition and powers of the Senate are established in Article One of the U.S. Constitution. Each...
Bob Dole
Bob Dole
Robert Joseph "Bob" Dole is an American attorney and politician. Dole represented Kansas in the United States Senate from 1969 to 1996, was Gerald Ford's Vice Presidential running mate in the 1976 presidential election, and was Senate Majority Leader from 1985 to 1987 and in 1995 and 1996...
and soccer
Football (soccer)
Association football, more commonly known as football or soccer, is a sport played between two teams of eleven players with a spherical ball...
star Pelé
Pelé
However, Pelé has always maintained that those are mistakes, that he was actually named Edson and that he was born on 23 October 1940.), best known by his nickname Pelé , is a retired Brazilian footballer. He is widely regarded as one of the greatest football players of all time...
). 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
Aphrodisiac
An aphrodisiac is a substance that increases sexual desire. The name comes from Aphrodite, the Greek goddess of sexuality and love. Throughout history, many foods, drinks, and behaviors have had a reputation for making sex more attainable and/or pleasurable...
s now call themselves "herbal viagra
Herbal viagra
Herbal viagra is a name that can be given to any herbal product advertised as treating erectile dysfunction. The name "herbal viagra" is taken from the brand name Viagra, under which drug company Pfizer sells sildenafil citrate, a drug that is used to treat erectile dysfunction...
" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", "Blue Diamond" as well as various other nicknames.
In 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
pills. By 2007, Viagra's global share had plunged to about 50 percent 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 February 2007, it was announced that Boots
Boots UK
Boots UK Limited , is a leading pharmacy chain in the United Kingdom, with outlets in most high streets throughout the country...
, the UK pharmacy chain, would try over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
sales of Viagra in stores in Manchester
Manchester
Manchester is a city and metropolitan borough in Greater Manchester, England. According to the Office for National Statistics, the 2010 mid-year population estimate for Manchester was 498,800. Manchester lies within one of the UK's largest metropolitan areas, the metropolitan county of Greater...
, England
England
England is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
. Men between the ages 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist
Pharmacist
Pharmacists are allied health professionals who practice in pharmacy, the field of health sciences focusing on safe and effective medication use...
.
Patent issues and expirations
A UKUnited Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
patent held by Pfizer on the use of PDE5 inhibitor
PDE5 inhibitor
A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis...
s (see below) as treatment of impotence was invalidated in 2000 because of obviousness
Inventive step and non-obviousness
The inventive step and non-obviousness reflect a same 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....
; this decision was upheld on appeal in 2002. But there are two other patents covering the methods for manufacturing Viagra, and Pfizer has maintained its monopoly on the drug in the UK.
Pfizer's patent on sildenafil citrate expired in Brazil in 2010. It was originally believed that Pfizer's patents would expire in the United States in March 2012., but an August 2011 federal district court case raises the prospect that at least one of Pfizer's patents will be valid until 2019.
External links
- Official Viagra Website
- Official Viagra UK Website
- Official Revatio Website
- prescribing information for Viagra and prescribing information for Revatio from PfizerPfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
- FDA Information
- MedlinePLUS information, including side effects
- U.S. National Library of Medicine: Drug Information Portal - Sildenafil