Viagra (Sildenafil citrate), a revolutionary drug for impotence treatment

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).
Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. VIAGRA is formulated as blue,film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

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.
Even though sildenafil is only available by prescription from a doctor, it was advertised directly to consumers on US 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”, 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 color 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 of Sildenafil

The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Pharmacokinetics and Metabolism

VIAGRA is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Absorption and Distribution

VIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Metabolism and Excretion

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects.
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.

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.
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.

Contraindications

Contraindications include:

When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), 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.

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.

Non-medical use

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’.”

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.

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

What special precautions should I follow before I start taking viagra?

Tell your doctor and pharmacist if you are allergic to sildenafil or any other medications.
Do not take sildenafil if you are taking taking or have recently taken nitrates such as isosorbide dinitrate (Isordil), isosorbide mononitrate (Imdur, ISMO), and nitroglycerin (Nitro-BID, Nitro-Dur, Nitroquick, Nitrostat, others). Nitrates come as tablets, sublingual (under the tongue) tablets, sprays, patches, pastes, and ointments. Ask your doctor if you are not sure whether any of your medications contain nitrates.
Do not take street drugs containing nitrates such as amyl nitrate and butyl nitrate (’poppers’) while taking sildenafil.
Tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take, especially alpha blockers such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), tamsulosin (Flomax), and terazosin (Hytrin); amiodarone (Cordarone, Pacerone); amlodipine (Norvasc) ; certain antifungals such as fluconazole (Diflucan), griseofulvin (Fulvicin, Grifulvin, Gris-PEG), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend);aprepitant (Emend); carbamazepine (Carbatrol, Epitol, Tegretol);cimetidine (Tagamet, Tagamet HB); clarithromycin (Biaxin, in Prevpac); cyclosporine (Neoral, Sandimmune);delaviridine (Rescriptor);dexamethasone (Decadron, Dexpak); diltiazem (Cardizem, Dilacor, Tiazac, others); efavirenz (Sustiva); erythromycin (E.E.S., E-Mycin, Erythrocin); fluoxetine (Prozac, Sarafem); fluvoxamine (Luvox); HIV protease inhibitors including atazanavir (Reyataz), indinavir (Crixivan), lopinavir (in Kaletra),nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Fortovase, Invirase); lovastatin (Advicor, Altocor, Mevacor); nefazodone; nevirapine (Viramune);other medications or devices to treat erectile dysfunction; phenobarbital; phenytoin (Dilantin, Phenytek); rifabutin (Mycobutin);rifampin (Rifadin, Rimactane); sertraline (Zoloft); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan);and zafirlukast (Accolate).
Tell your doctor what herbal products you are taking or plan to take, especially St. John’s wort.
Tell your doctor if you smoke and if you have ever had an erection that lasted for several hours. Also tell your doctor if you have or have ever had a bleeding disorder, a stomach ulcer; heart, kidney, or liver disease; a heart attack; an irregular heartbeat; chest pain; a stroke; high or low blood pressure; high cholesterol; blood cell problems such as sickle cell anemia (a disease of the red blood cells), multiple myeloma (cancer of the plasma cells), or leukemia (cancer of the white blood cells); conditions affecting the shape of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease); or diabetes. Also tell your doctor if you or any of your family members have or have ever had an eye disease such as retinitis pigmentosa or if you have ever had severe vision loss, especially if you were told that the vision loss was caused by a blockage of blood flow to the nerves that help you see. Tell your doctor if you have ever been advised by a health care professional to avoid sexual activity for medical reasons or if you have ever experienced chest pain during sexual activity.
You should know that sildenafil is only for use in males. Women should not take sildenafil, especially if they are or could become pregnant or are breast-feeding. If a pregnant woman takes sildenafil, she should call her doctor.
If you are having surgery, including dental surgery, tell your doctor or dentist that you take sildenafil.
You should know that sexual activity may be a strain on your heart, especially if you have heart disease. If you have chest pain during sexual activity, call your doctor immediately and avoid sexual activity until your doctor tells you otherwise.
Tell all your health care providers that you are taking sildenafil. If you ever need emergency medical treatment for a heart problem, the health care providers who treat you will need to know when you last took sildenafil.

Final Tips

You will not get an instant erection. You must be aroused for VIAGRA to work
VIAGRA usually works in about 30 minutes
VIAGRA works for 4 hours, so you can take your time
After sex, your erection will go away
To get the fastest results, take VIAGRA on an empty stomach or after eating a low-fat meal

Sources: pfizer (pdf), wikipedia, medlineplus