Everything about Viagra totally explained
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).
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.
(External Link
) 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.
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.
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) 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 shouldn't 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 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 isn't 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.
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.
Contraindications
Contraindications include:
Side effects
Amongst sildenafil's rare but serious adverse effects are:
priapism, severe
hypotension,
myocardial infarction,
ventricular arrhythmias,
stroke and increased
intraocular pressure.
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.
Some sildenafil users have complained of seeing everything tinted blue (
cyanopsia). . 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 and a number of studies have linked sildenafil use with
nonarteritic anterior ischemic optic neuropathy.
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.
When used with an
alpha blocker,
hypotension (low blood pressure) may occur, but this effect doesn't occur if they're taken at least four hours apart.
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, 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.
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.
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. 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.
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.
Non-medical use
Aphrodisiac
Sildenafil is commonly and increasingly used as an
aphrodisiac, for example to increase
sexual desire. However, there's no clinical evidence that it has aphrodisiac activity, because it doesn't 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.
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'."
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.
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. Their research was published in the
Proceedings of the National Academy of Sciences.
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.Further Information
Get more info on 'Viagra'.
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