Sildenafil
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Sildenafil
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| Systematic (IUPAC) name | |
| 1-[4-ethoxy-3-(6,7-dihydro-1-methyl- 7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine citrate |
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| Identifiers | |
| CAS number | |
| ATC code | G04 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C22H30N6O4S |
| Mol. mass | base: 474.6 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 40% |
| Metabolism | Hepatic |
| Half life | 3-4h |
| Excretion | CYP3A4 |
| Therapeutic considerations | |
| Pregnancy cat. |
N/A |
| Legal status |
℞ Prescription only |
| Routes | Oral |
Sildenafil citrate, sold under the names Viagra, Revatio and under various other names, is a drug used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH), developed by the pharmaceutical company Pfizer. Its primary competitors on the market are tadalafil (Cialis), and vardenafil (Levitra).
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[edit] History
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic cardiovascular disease). The first clinical trials were conducted in Morriston Hospital in Swansea.[2] Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.[1][2] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.[3] It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim which Pfizer disputes.[4] Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.
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 Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation," often a simple web questionnaire. The "Viagra" name has become so well known that many fake aphrodisiacs now call themselves "herbal Viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", as well as various other nicknames.
In February 2007, it was announced that Boots the Chemist would trial over the counter sales of Viagra in stores in Manchester, England. Men aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[5]
Pfizer's worldwide patents on sildenafil citrate will expire in 2011–2013. The UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.
[edit] Mechanism of action
Part of the physiological process of erection involves the parasympathetic nervous system causing the release of nitric oxide (NO) in the corpus cavernosum of the penis. NO binds to the receptors of the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries, resulting in increased inflow of blood and an erection.
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 hepatic enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, there may be a delay in absorption of sildenafil and the peak effect might be reduced slightly as the plasma concentration will be lowered.
[edit] Dosage and price
As with all prescription drugs, proper dosage is at the discretion of a licensed medical doctor. 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.
It is usually recommended to start with a dosage of 50 mg and then lower or raise the dosage as appropriate. The drug is sold in three dosages (25, 50, and 100 mg), all three costing about US$10 per pill. Name-brand Viagra sildenafil is not scored and a fairly hard coating makes it more difficult to accurately cut the pills in half, even with a pill cutter.
The dosage for pulmonary arterial hypertension (Revatio) is one 20 mg tablet three times a day.
Viagra pills are blue and diamond-shaped with the words "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. Words are not printed on the pills.
Revatio pills, which are used for PAH, are white, round, film-coated tablets imprinted with "RVT 20" on one side and "Pfizer" on the other.
[edit] Market structure
In 2000, Viagra sales accounted for 92 per cent of the global market for prescribed Erectile Dysfunction pills.(pdf) By 2007, Viagra's global share had plunged to about 50 percent due to entry of Cialis and Levitra, along with several other counterfeits and clones.
[edit] Contraindications
Contraindications include:
- When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")[6]
- In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors
- Severe hepatic impairment (decreased liver function)
- Severe impairment in renal function
- Hypotension (low blood pressure)
- Recent stroke or heart attack
- Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)
[edit] Side effects
Amongst sildenafil's rare but serious adverse effects are: priapism, severe hypotension, myocardial infarction, ventricular arrhythmias, stroke and increased intraocular pressure.[citation needed]
Common side effects include sneezing, headache, flushing, dyspepsia, palpitations and photophobia.
Care should be exercised by patients who are also taking Protease inhibitors 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.[citation needed]
Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). [7]. Some complained of blurriness and loss of peripheral vision. In May of 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment[8] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.[9][10][11][12][13][14]
In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors.[15]
When used with an alpha blocker, hypotension (low blood pressure) may occur, but this effect does not occur if they are taken at least four hours apart.[16]
[edit] Other uses
[edit] Pulmonary hypertension
As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease 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.[17]
[edit] Raynaud's phenomenon
In 2005, Dr. Roland Fries and colleagues reported that sildenafil cut the frequency of Raynaud's phenomenon attacks, reduced their duration by roughly one half, and more than quadrupled the mean capillary blood velocity. This was a double-blind, placebo-controlled crossover trial and the patients had both the primary and secondary forms and had all discontinued the more conventional treatments for this.[18]
[edit] Altitude sickness
Sildenafil has been shown to be useful for the prevention and treatment of High altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers.[19][20] While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, particularly in situations where the standard treatment of rapid descent has been delayed for some reason.[21]
[edit] Duchenne/Becker Muscular Dystrophy
Sildenafil has recently been used to enhance cGMP signaling, specifically downstream and independent of NO formation, in dystrophin-deficient mouse hearts. Chronic treatment improved contractile performance, myocardial metabolic status, and sarcolemmal integrity, highlighting its potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies. [22]
[edit] Non-medical use
[edit] Aphrodisiac
Sildenafil is commonly and increasingly used as an aphrodisiac, i.e. to increase sexual desire. However, there is no clinical evidence that it has aphrodisiac activity, because it does not have any direct effect on the brain, although increased ability to attain an erection may be interpreted as increased sexual arousal by users of these drugs.
[edit] Recreational use
Viagra's popularity with young adults has increased over the years.[23] It is sometimes used recreationally. Some users mix Viagra with methylenedioxymethamphetamine (MDMA, ecstasy) in an attempt to compensate for the side effect common to many amphetamines of erectile dysfunction, a combination known as "sextasy", "rockin' and rollin'", or 'trail mix'."
[edit] Prevention of plant wilting
A low-concentration solution of sildenafil in water significantly prolongs the time before cut flowers wilt; one experiment showed a doubling in time from one week to two weeks. The mechanism of action is similar to that in humans: nitric oxide leads to the production of cGMP whose degradation by PDE5 is inhibited by sildenafil.[24]
[edit] 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 Viagra aids jet lag recovery in hamsters.[25] Their research was published in the Proceedings of the National Academy of Sciences.[26]
[edit] Chemical synthesis
The preparation steps for synthesis of Viagra (sildenafil citrate) are as follows:
- Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate.
- Hydrolysis with aqueous NaOH to free acid.
- Nitration with oleum/fuming nitric acid.
- Carboxamide formation with refluxing thionyl chloride/NH4OH.
- Reduction of nitro group to amino.
- Acylation with 2-ethoxybenzoyl chloride.
- Cyclization.
- Sulfonation to the chlorosulfonyl derivative.
- Condensation with 1-methylpiperazine.[27]
[edit] See also
- Tadalafil (Cialis)
- Vardenafil (Levitra)
- Yohimbine
[edit] References
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This article needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (March 2008) |
- ^ Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int J Impot Res 8 (2): 47–52. PMID 8858389.
- ^ Terrett NK et al (1996). "Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction". Bioorg Med Chem Lett 6: 1819–1824. doi:.
- ^ Kling J (1998). "From hypertension to angina to Viagra". Mod Drug Discov 1: 31–38.
- ^ Bellis M. Viagra, the patenting of an aphrodisiac. About.com.
- ^ Over-the-counter Viagra piloted. British Broadcasting Corporation (2007-02-11).
- ^ Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM (1999). "ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association". Journal of the American College of Cardiology 33 (1): 273-82. doi:. PMID 9935041.
- ^ Viagra and vision. visionweb (n.d.).
- ^ Alert for Healthcare Professionals: Sildenafil citrate (marketed as Viagra). United States Food and Drug Administration (July 2005).
- ^ Pomeranz HD and Bhavsar AR (2005). "Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases". J Neuroophthalmol 25 (1): 9-13. PMID 15756125.
- ^ Egan R and Pomeranz H (2000). "Sildenafil (Viagra) associated anterior ischemic optic neuropathy". Arch Ophthalmol 118 (2): 291-2. PMID 10676804.
- ^ Pomeranz HD, Smith KH, Hart WM, Egan RA (2002). "Sildenafil-associated nonarteritic anterior ischemic optic neuropathy". Ophthalmology 109 (3): 584-7. doi:. PMID 11874765.
- ^ Cunningham AV and Smith KH (2001). "Anterior ischemic optic neuropathy associated with viagra". J Neuroophthalmol 21 (1): 22-5. PMID 11315976.
- ^ Boshier A, Pambakian N, Shakir SA (2002). "A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil". Int J Clin Pharmacol Ther 40 (9): 422-3. PMID 12358159.
- ^ Akash R, Hrishikesh D, Amith P, Sabah S (2005). "Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra". J Ocul Pharmacol Ther 24 (4): 315-7. PMID 16117695.
- ^ FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. Food and Drug Administration (2007-10-18). Retrieved on 2007-12-08.
- ^ Kloner RA (2005). "Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions". Am J Cardiol 96 (12B): 42M-46M. doi:. PMID 16387566.
- ^ Pfizer, Inc. (June 6, 2005). FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension. 2005 News Releases. Pfizer. Retrieved on December 27, 2005.
- ^ Fries, Roland; Kaveh Shariat, Hubertus von Wilmowsky, and Michael Böhm (November 8, 2005). "Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy". Circulation 112 (19): 2980-5. doi:. PMID 16275885.
- ^ Richalet JP, Gratadour P, Robach P, et al (2005). "Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension". Am. J. Respir. Crit. Care Med. 171 (3): 275-81. doi:. PMID 15516532.
- ^ Perimenis P (2005). "Sildenafil for the treatment of altitude-induced hypoxaemia". Expert Opin Pharmacother 6 (5): 835-7. doi:. PMID 15934909.
- ^ Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt. Med. Biol. 8 (2): 139-46. doi:. PMID 17584008.
- ^ {{cite journal |author=Khairallah M, Khairallah RJ, Young ME, et al |title=Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency. |journal=Proc. Nat. Acad. Sci. U.S.A. |volume=105 |issue=19 |pages=7028-33 |year=2008 |pmid=18474859
- ^ Peterson K. "Young men add Viagra to their drug arsenal", USAToday, 2001-03-21.
- ^ Siegel-Itzkovich J (1999). "Viagra makes flowers stand up straight". Student BMJ (9).
- ^ [1]
- ^ Agostino PV, Plano SA, Golombek DA (2007). "Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules". Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9834-9. doi:. PMID 17519328.
- ^ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev 2005 (1): 88-97. doi:.
[edit] External links
- Home page for Viagra
- Home page for Revatio
- Pfizer Pharmaceutical (Company website) - manufacturer of Viagra; prescribing information for Viagra and prescribing information for Revatio available in PDF format.
- FDA Web Site for Viagra Consumer Information
- FDA current Viagra label (a form of clinical information and report)
- MedlinePLUS drug Information - Side Effects of sildenafil
- How Viagra Works - Howstuffworks article
- Does Viagra Keep Flowers From Wilting?
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