Sildenafil

Sildenafil
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
Identifiers
CAS number	139755-83-2
ATC code	G04BE03
PubChem	5281023
DrugBank	APRD00556
ChemSpider	56586
Chemical data
Formula	C22H30N6O4S
Mol. mass	base: 474.6 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	40%
Metabolism	Hepatic (mostly CYP3A4, also CYP2C9)
Half life	3 to 4 hours
Excretion	Fecal (80%) and renal (around 13%)
Therapeutic considerations
Licence data	EU, US
Pregnancy cat.	B(US)
Legal status	℞ Prescription only
Routes	Oral

Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction (male impotence) and pulmonary arterial hypertension (PAH). It was developed and is being marketed by the pharmaceutical company Pfizer. It acts by inhibiting cGMP specific phosphodiesterase type 5, an enzyme that 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).

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 heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.^[1] 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.^[2][3] 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 oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.^[4] 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.^[5] 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 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 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 2000, Viagra sales accounted for 92 percent of the global market for prescribed erectile dysfunction pills.^[6] By 2007, Viagra's global share had plunged to about 50 percent^[7] due to several factors, including the entry of Cialis and Levitra, along with several other counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors.^[8][9]

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.^[10]

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.^{[11] [12]}

Mechanism of action

The mechanism of action of Sildenafil citrate involves 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.^[13]

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.^[13] 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 enzymes and excreted by both the liver and kidneys. 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.^[14]

Uses

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). It use is now standard treatment for erectile dysfunction in all settings, including diabetes.^[15]

People on antidepressants 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.^[16] Following up to earlier reports from 1999,^[17] the same researchers found that sildenafil was able to improve sexual function in female patients on antidepressants as well.^[18]

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.^[19]

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.^[20][21] 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.^[22]

Use in sports

Professional sports players have been using drugs such as Viagra thinking that the opening of their blood vessels will enrich their muscles, therefore enhancing their performance.^[23]

Non-medical use

Recreational use

Viagra's popularity with young adults has increased over the years.^[24] It is sometimes used recreationally, though this use is somewhat pointless in young, healthy men, as they receive no benefit from the drug.^[24] Some users mix Viagra with methylenedioxymethamphetamine (MDMA, ecstasy) or other stimulants 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'." Mixing with amyl nitrite is particularly dangerous, and is potentially fatal.^[24]

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.^[25]

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.^[26] Their research was published in the Proceedings of the National Academy of Sciences.^[27]

Dosage

Viagra

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. 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 (or even 25 mg) and then lower or raise the dosage as appropriate.

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. ^[28]

Contraindications

Contraindications include:

• When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")^[29]
• 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)

Side effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia and blurred vision.^[30] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).^[31]. Some complained of blurriness and loss of peripheral vision. In May 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment^[32] and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.^{[33][34][35][36][37][38]}

Rare but serious adverse effects found through postmarketing surveillance include priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure and sudden hearing loss.^[30] 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 as the result of these postmarketing reports.^[39]

Interactions

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.

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.^[40]

Chemical synthesis

The preparation steps for synthesis of Viagra (sildenafil citrate) are as follows:^[41]

1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate.
2. Hydrolysis with aqueous NaOH to free acid.
3. Nitration with oleum/fuming nitric acid.
4. Carboxamide formation with refluxing thionyl chloride/NH₄OH.
5. Reduction of nitro group to amino.
6. Acylation with 2-ethoxybenzoyl chloride.
7. Cyclization.
8. Sulfonation to the chlorosulfonyl derivative.
9. Condensation with 1-methylpiperazine.

See also

• Tadalafil (Cialis)
• Vardenafil (Levitra)

References

External links

• Official Viagra Website
• Official Revatio Website
• Official Pfizer Website – manufacturer of Viagra; prescribing information for Viagra and prescribing information for Revatio
• FDA Consumer Information
• MedlinePLUS Information on Side Effects