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Vardenafil (INN) is a PDE5 inhibitor used in the treatment of erectile dysfunction. It can assist men with this disorder in achieving and maintaining an erection during sexual activity. It is commonly marketed under the trade name Levitra (Bayer AG).

PDE5 Inhibitors
The cyclic nucleotide phosphodiesterases constitute a group of enzymes that catalyze the hydrolysis of the cyclic nucleotides cyclic AMP and cyclic GMP. They exist in different molecular forms and are unevenly distributed throughout the body. These multiple forms or subtypes of phosphodiesterase were initially isolated from rat brain by Uzunov and Weiss in 1972 and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues (Weiss,1975; Fertel and Weiss, 1976). The potential for selective phosphodisterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction has now come to pass in a variety of fields, one of which is in the pharmacologic treatment of erectile dysfunction

One of the forms of phophodiesterase is termed PDE5. The prescription PDE5 inhibitors sildenafil (Viagra®), vardenafil (Levitra®) and tadalafil (Cialis®) are prescription drugs which are taken orally. They work by blocking the action of PDE5, which causes cGMP to degrade. CGMP specific phosphodiesterase type 5|cGMP]] causes the smooth muscle of the arteries in the penis to relax, allowing the corpus cavernosum to fill with blood.

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” (where xx stands for “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. 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. 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. Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.

Viagra is available as blue pills with a characteristic shapeEven 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 and Football star Pele). 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”, as well as 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 was 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 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.

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 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.

Marketing
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Contraindications. When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate, sodium nitroprusside, amyl nitrite (”poppers”)
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. 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 sildenafil 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 and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy.When used with an alpha blocker, take them at least four hours apart to avoid hypotension.

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 atrium 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.

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

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 that will occur.

Recreational use. Viagra’s popularity with young adults has increased over the years. 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’.

Chemical Synthesis. The preparation steps for synthesis of Viagra (sildenafil citrate) are as follows:

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)

There are no formal tests to diagnose erectile dysfunction. Some blood tests are generally done to exclude underlying disease, such as diabetes, hypogonadism and prolactinoma. Impotence is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease such as coronary artery disease and peripheral vascular disease.

A useful and simple way to distinguish between physiological and psychological impotence is to determine whether the patient ever has an erection. If never, the problem is likely to be physiological; if sometimes (however rarely), it is more likely to be psychological. The current diagnostic and statistical manual of mental diseases (DSM-IV) has included a listing for impotence.

Clinical tests used to diagnose ED
Duplex ultrasound
Duplex ultrasound is used to evaluate blood flow, venous leak, signs of atherosclerosis, and scarring or calcification of erectile tissue. Injecting prostaglandin, a hormone-like stimulator produced in the body, induces erection. Ultrasound is then used to see vascular dilation and measure penile blood pressure. Measurements are compared to those taken when the penis is flaccid.
Penile nerves function
Tests such as the bulbocavernosus reflex test are used to determine if there is sufficient nerve sensation in the penis. The physician squeezes the glans (head) of the penis, which immediately causes the anus to contract if nerve function is normal. A physician measures the latency between squeeze and contraction by observing the anal sphincter or by feeling it with a gloved finger inserted past the anus. Specific nerve tests are used in patients with suspected nerve damage as a result of diabetes or nerve disease.
Nocturnal penile tumescence (NPT)
It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge.
Penile biothesiometry
This test uses electromagnetic vibration to evaluate sensitivity and nerve function in the glans and shaft of the penis. A decreased perception of vibration may indicate nerve damage in the pelvic area, which can lead to impotence.
Penile Angiogram
Invasive test - allows visualization of the circulation in the penis and is used during the repair of a priapism.
Dynamic Infusion Cavernosometry
(Abbreviated DICC) technique in which fluid is pumped into the penis at a known rate and pressure. It gives a measurement of the vascular pressure in the corpus cavernosum during an erection. To do this test, a vasodilator like prostaglandin E-1 is injected to measure the rate of infusion required to get a rigid erection and to help find how severe the venous leak is.
Corpus Cavernosometry
Cavernosography is an adjunct to Dynamic Infusion Cavernosometry, where a contrast material is injected and then it is x-rayed to visualize any leakage.
Digital Subtration Angiography
In DSA, the images are acquired digitally. The computer crates a mask from lower-contrast x-rays of the same area and digitally isolates the blood vessels (this is done manually through darkroom masking with traditional angiography).
Magnetic resonance angiography (MRA)
This is similar to magnetic resonance imaging. Magnetic resonance angiography uses magnetic fields and radio waves to provide detailed images of the blood vessels. Doctors may inject a “contrast agent” into the patient’s bloodstream that causes vascular tissues to stand out against other tissues. The contrast agent provides for enhanced information regarding blood supply and vascular anomalies. Aside from the IV used to introduce the contrast material into the bloodstream, magnetic resonance angiography is noninvasive and painless.

Erectile dysfunction is characterized by the inability to maintain an erection. Normal erections during sleep and in the early morning suggest a psychogenic cause, while loss of these erections may signify underlying disease, often cardiovascular in origin. Other factors leading to erectile dysfunction are diabetes mellitus (causing neuropathy) or hypogonadism (decreased testosterone levels due to disease affecting the testicles or the pituitary gland).

Tadalafil (Cialis) is a medicine that should be accepted orally. This drug is applied for the treatment of impotence (the inability to attain or maintain a penile erection). It belongs to in a class of drugs called phosphodiesterase inhibitors. This class also includes sildenafil (Viagra) and vardenafil (Levitra). Erection of the penis is caused by the filling of the penis with blood. Filling occurs because the blood vessels bringing blood to the penis extand in size, that’s why the penis is filled by a plenty of blood. At the same time, the blood vessels that carry blood away from the penis reduce in size and remove less blood from the penis. Sexual stimulation that leads to an erection causes the production and emission of nitric oxide in the penis. The nitric oxide causes an enzyme called guanylate cyclase which is necessary for production of cyclic guanosine monophosphate (cGMP). This chemical compound is responsible for extanding and redusing the size of the blood vessels carrying blood to and from the penis. These transformations lead to erection. Then the cGMP is destroyed by another enzyme called phosphodiesterase-5, the blood vessels return to their normal size, blood leaves the penis, and the erection ends. Tadalafil (Cialis) averts cGMP from destroying by phosphodiesterase-5 so that cGMP stays around longer. The longer existence of cGMP causes more prolonged filling of the penis with blood. Tadalafil (Cialis) was approved by the FDA in November, 2003.