Article: Sildenafil

8937-220px-sildenafil-sildenafil-citrate.png
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 171599-83-0
ATC code G04BE03
PubChem 5281023
DrugBank APRD00556
Chemical data
Formula C22H30N6O4S · C6H8O7
Mol. weight base: 474.6 g/mol
salt: 666.7 g/mol
SMILES O=S(=O)(N1CCN(C)CC1)c4cc(C=2NC(=O)
c3n(C)nc(CCC)c3N=2)c(OCC)cc4
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

N/A

Legal status

Rx only/POM

Routes Oral

Sildenafil citrate, sold under the names Viagra, Revatio and generically 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. Viagra pills are blue and diamond-shaped with the words "Pfizer" on one side and "VGR xx" (with xx representing 25, 50 or 100, the dose of that pill in milligrams) on the other. 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. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). 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 only available by prescription from a doctor, it was advertised directly to consumers on US TV (famously being endorsed by Bob Dole). Numerous sites on the Internet offer Viagra for sale after an "online consultation," a mere 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", and goes by various other nicknames.

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 has been invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

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) in the corpus cavernosum, 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 cGMP in the corpus cavernosum, resulting in better erections. Without sexual stimulation and no 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.

Some reports have claimed sildenafil causes enhanced sexual pleasure for women by increasing blood flow to the sexual organs. This lacks firm evidence, and it has also been suggested that this is part of an effort to invent a new disease - female sexual dysfunction - thus doubling the potential size of the market for this class of drugs.

Dosage and price

As with all prescription drugs, proper dosage is at the discretion of a licensed medical doctor. The dose of sildenafil is 25 mg to 100 mg taken once per day between 30 minutes to 4 hours before 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. Sildenafil is not scored and it is not advisable to cut it to change dosage since the active compound is not distributed homogenously in the tablet.

Contraindications and side effects

Contraindications include:

Amongst sildenafil's serious adverse effects are: priapism, severe hypotension, myocardial infarction, ventricular arrhythmias, sudden death, stroke and increased intraocular pressure.

Common side effects include sneezing, headache, flushing, dyspepsia, prolonged erections, palpitations and photophobia. Visual changes including blurring of vision and a curious bluish tinge have also been reported.

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.

Some Viagra users have 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[6] and a number of studies have linked Viagra use with nonarteritic anterior ischemic optic neuropathy[7][8][9][10][11][12].

Other uses

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, decreasing pulmonary arterial resistance and pressure, and thus the strain on the right side of the heart thus improving symptoms of right-sided heart failure. Because the distribution of PDE-5, which is primarily in the arterial wall smooth muscle in 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, avoiding confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclins therapies for this condition[13].

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[14].

Cognitive enhancement

A recent study performed at the National Institute on Aging's Gerontology Research Center shows that sildenafil citrate may help to attenuate cognitive deficits associated with aging. Scientists found that in rats, administration of sildenafil citrate partially reversed the memory impairment produced by L-NAME, a nitric oxide synthase inhibitor implicated in the same cGMP signal transduction pathway as sildenafil. While it is too early to draw a firm conclusion, researchers seem optimisitic about the drug's promise in treating age-related neurodegeneration (PMID 16320087).

Analgesia

Several studies have determined that sildenafil citrate demonstrates anti-nociceptive properties in rodents. While the effect seems to be greatest in diabetic animals, non-diabetic animals, too, show significant elevation in pain threshold (PMID 15452368). Current evidence seems to suggest that the cGMP that accumulates as a result of Phosphodiesterase 5 inhibition interacts with the cholinergic system to mediate this pain-reducing effect (PMID 15088685).

Drug abuses

Aphrodisiac

Sildenafil is commonly and increasingly used as an aphrodisiac. While there is no clinical evidence that it has aphrodisiac activity, many seem to believe it will improve sexual performance as well as erectile function and enhance the sexual experience.

Recreational use

Viagra's popularity with young adults have increased over the years[15]. It is sometimes used recreationally. Some users mix Viagra with methylenedioxymethamphetamine (MDMA, ecstasy), a combination known as Sextasy.

See also

  • Tadalafil (Cialis)
  • Vardenafil (Levitra)

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