Sildenafil

• 1. Introduction

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  Sildenafil, best known as Viagra, is a drug that once earned an Ig Nobel Prize for helping hamsters recover from jet lag. The 2007 Ig Nobel Prize in aviation went to Patricia V. Agostino, Santiago A. Plano and Diego A. Golombek of Universidad Nacional de Quilmes in Argentina. The result sounds like a joke, yet it suits a molecule that keeps turning up in places nobody planned. Sildenafil treats erectile dysfunction and a lung condition called pulmonary arterial hypertension. It has been tried on damaged fingers and toes, and on people climbing to high altitude. How did a compound from a British laboratory become one of the most recognizable brand names on earth? What does it actually do inside the body? And why do counterfeiters, patent lawyers and regulators in country after country still argue over a single small pill?

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• 2. A Heart Drug Repositioned

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  Pfizer first discovered sildenafil in 1989, while searching for a treatment for angina. The compound carried the laboratory code UK-92,480. It was made by a group of pharmaceutical chemists led by Simon Campbell at Pfizer's research site in Sandwich, Kent, in England. Researchers first studied it as a possible treatment for high blood pressure and for angina, a symptom of ischaemic heart disease.

  The first clinical trials took place at Morriston Hospital in Swansea. Phase I trials, directed by Ian Osterloh, suggested the drug did little for angina. They also showed that it could produce marked erections. Pfizer therefore chose to market it for erectile dysfunction instead of angina. That decision has become an often-cited example of drug repositioning.

  The drug was patented in 1996. On the 27th of March 1998, the United States Food and Drug Administration approved it for erectile dysfunction, making it the first oral treatment for the condition approved in the United States. It went on sale in the US later that year. It was also approved in the European Union in 1998.

  The drug soon became a great success. Annual sales of Viagra peaked in 2008 at US$1.934 billion.

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• 3. How It Works

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  Robert F. Furchgott, Ferid Murad and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent studies of nitric oxide and smooth muscle. Their work mapped the chemical pathway that sildenafil exploits. During sexual stimulation, nitric oxide in the corpus cavernosum of the penis binds to guanylate cyclase receptors. That raises levels of a messenger molecule called cGMP, which relaxes smooth muscle and widens the arteries. More blood then flows into the spongy tissue of the penis, producing an erection.

  An enzyme called phosphodiesterase type 5, or PDE5, normally breaks cGMP down. Sildenafil is a potent and selective inhibitor of PDE5. Its molecular structure resembles cGMP, so it competes for the enzyme and leaves more cGMP in place. Without sexual stimulation, the nitric oxide and cGMP system is never switched on. For that reason sildenafil does not cause arousal and should not cause an erection by itself. It also widens blood vessels in the lungs. Tadalafil, sold as Cialis, and vardenafil, sold as Levitra, work by the same mechanism.

  The liver does most of the cleanup, mainly through the enzyme CYP450 3A4 and, to a lesser degree, CYP2C9. The main product is N-desmethylated sildenafil. It binds PDE receptors with about 40% of the strength of the parent drug and accounts for about 20% of the effect. About 80% of an oral dose leaves in the feces, and around 13% leaves in the urine. A high-fat meal slows things down. It delays the peak concentration by around one hour and lowers that peak by nearly one third.

  Taken by mouth for erectile dysfunction, sildenafil produces erections after an average of 27 minutes, with a range of 12 to 70 minutes. Dissolved under the tongue, it acts after an average of 15 minutes, though the effect lasts only about 40 minutes.

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• 4. Other Medical Uses

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  For pulmonary arterial hypertension, sildenafil improves some markers of the disease. It does not appear to change the risk of death or of serious side effects. In erectile dysfunction, by contrast, it is now one of the standard treatments, including for men with diabetes mellitus. Tentative evidence suggests it may also help men whose erectile dysfunction is caused by antidepressants. Whether it works for sexual dysfunction in women remains unclear.

  Doctors also prescribe it off-label for secondary Raynaud's phenomenon. In that condition, spasms in the small blood vessels of the fingers and toes can cause severe ischemia and ulcers. Sildenafil and related PDE5 inhibitors have moderate efficacy at reducing how often and how long these spasms last. As of 2016, their wider role in Raynaud's was not clear.

  Altitude has been another testing ground. Sildenafil has shown some potential for improving exercise performance at high elevation, but its overall efficacy is uncertain. It has also been studied for high-altitude pulmonary edema, and its use for that purpose is currently not recommended.

  Professional athletes have been documented using sildenafil as well. They believe that opening their blood vessels will enrich their muscles with blood and improve performance.

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• 5. Blue Tints and Warnings

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  In July 2005, the US Food and Drug Administration updated the labels of Cialis, Levitra and Viagra after a small number of reports of sudden vision loss. The agency said it could not determine whether the drugs caused the loss of eyesight or whether other factors such as high blood pressure or diabetes were responsible. A later careful review of pooled clinical trial data found no evidence of increased risk of non-arteritic anterior ischemic optic neuropathy or other eye problems from PDE5 inhibitors.

  Some users of sildenafil have complained of seeing everything tinted blue, a condition called cyanopsia. The explanation lies in the retina. Sildenafil is selective for PDE5 but has some affinity for PDE6, the phosphodiesterase found in the eye. Other users reported blurriness and loss of peripheral vision. The most common complaints in clinical trials were milder: headache, flushing, indigestion and nasal congestion.

  Postmarketing surveillance has turned up rare but serious problems. These include prolonged erections, severe low blood pressure, heart attack, ventricular arrhythmias, stroke, increased pressure inside the eye and sudden hearing loss. In October 2007 the FDA announced that all PDE5 inhibitors needed a more prominent warning about the risk of sudden hearing loss.

  Interactions can be serious. Protease inhibitors used against HIV slow the breakdown of sildenafil and multiply its levels in the blood. People taking them are advised to limit use to no more than one 25 mg dose every 48 hours. Erythromycin and cimetidine also interfere with its metabolism. Taking sildenafil with an alpha-1 blocker can lower blood pressure, but not if the two are taken at least 4 hours apart.

  Nitric oxide donors are off limits, including nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and sodium nitroprusside. So are soluble guanylyl cyclase stimulators such as riociguat. Sildenafil should also be avoided entirely when underlying cardiovascular risk makes sexual activity inadvisable.

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• 6. Misuse and Counterfeits

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  A 25 mg dose of sildenafil, in one study of recreational use, produced no significant change in erectile quality. It did shorten the postejaculatory refractory time, and the control group showed a significant placebo effect. Even so, the drug's popularity with young adults has grown over the years. Some take it believing it raises libido, improves performance or permanently increases penis size. Studies suggest it has little effect in people without erectile dysfunction.

  Use without a prescription is especially high among users of illegal drugs. Some mix sildenafil with MDMA, other stimulants or opiates to offset the erectile dysfunction those drugs can cause. The combinations have street names including "sextasy", "rockin' and rollin'", "hammerheading" and "trail mix". Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal. Doctors and forensic investigators can measure sildenafil, or its main active metabolite N-desmethylsildenafil, in plasma, serum or whole blood to confirm poisoning or investigate a fatal overdose.

  A 2012 Pfizer study found that around 80% of websites claiming to sell Viagra were selling counterfeits. Viagra is one of the most counterfeited medicines in the world. Fake tablets are generally cheaper, and they have been found to contain blue printer ink, amphetamines, metronidazole, boric acid and rat poison. An October 2023 release said erectile dysfunction medicines made up 22% of drugs seized by Interpol, more than any other kind.

  A second problem is the analogs. Acetildenafil and other synthetic relatives of sildenafil have turned up as hidden ingredients in over-the-counter "herbal" aphrodisiacs. They have never gone through rigorous testing, so their side effects are unknown. Banning them is slow, because laws on designer drugs target copies of illegal drugs, not copies of prescription medicines. The FDA has banned numerous products sold as Eurycoma longifolia that contained only sildenafil analogs, and sellers typically just rename them.

  The problem has not gone away. In 2026 a chocolate syrup called Boner Bears, from Lockout Supplements, was recalled through the FDA because it contained sildenafil as an undisclosed ingredient.

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• 7. Selling Viagra

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  Former United States Senator Bob Dole and football star Pelé both endorsed Viagra on television. Sildenafil is available in the US only by prescription, yet it was advertised directly to consumers. Direct advertising of prescription drugs was then permitted only in the United States and New Zealand. Viagra and similar products, termed sexuopharmaceuticals, spawned new styles of specialised marketing. Viagra became a cultural icon, and it is believed to have contributed significantly to norms around male sexuality.

  One author has argued that the advertising was deceptive. The drug acts only on blood vessels in the penis, but advertisements routinely showed couples hugging, smiling and dancing.

  Viagra had 92% of the global market for prescribed erectile dysfunction pills in 2000. By 2007 its share had fallen to about 50%. The causes included the arrival of Cialis and Levitra, a flood of counterfeits and clones, and reports of vision loss among users of PDE5 inhibitors. In 2008 the FDA forced Pfizer to remove an advergame for Viagra called Viva Cruiser from Forbes, because the game failed to disclose risk information.

  The route to the customer kept changing. Numerous internet sites offered Viagra after an online consultation that was often a simple web questionnaire. In February 2007 the UK pharmacy chain Boots announced a trial of over-the-counter sales in Manchester. Men aged 30 to 65 could buy four tablets after talking to a pharmacist. In May 2013 Pfizer told the Associated Press it would begin selling the drug directly to people on its own website.

  In 2017 the Medicines and Healthcare products Regulatory Agency allowed a 50 mg formulation called Viagra Connect to be sold without a prescription across the UK from early 2018. A pharmacist consultation is still required. Customers over 18 can buy an unlimited number of pills. New Zealand had already reclassified sildenafil in 2014 so that pharmacists could sell it over the counter. That change is thought to have reduced internet sales and to have been safer, because men could be referred for medical advice when appropriate.

  In England, prescriptions for sildenafil rose from 1,042,431 in 2006 to 2,958,199 in 2016.

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• 8. The Patent Battles

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  On the 8th of November 2012, the Supreme Court of Canada ruled that Pfizer's patent 2,163,446 on Viagra was invalid from the start. Pfizer had not given full disclosure in its application, as the Patent Act requires. The court wrote, "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to 'game' the system in this way. This, in my view, is the key issue in this appeal." The case was Teva Canada Ltd. v. Pfizer Canada Inc.

  Teva Canada launched a generic called Novo-Sildenafil on the day of the decision, and Pfizer cut its Canadian price to stay competitive. On the 9th of November 2012, Pfizer asked for a rehearing, arguing that the court had exceeded its jurisdiction by voiding the patent. On the 22nd of April 2013, the Supreme Court of Canada invalidated the patent altogether. Earlier, in June 2010, Canada's Federal Court had found Pfizer's separate patent for Revatio invalid, in an application by Ratiopharm.

  The United States was different. Pfizer filed one patent in 1992 covering sildenafil for cardiovascular disease, later sold as Revatio. It filed a second in 1994 covering the use for erectile dysfunction, sold as Viagra. The substance is identical under both names. Generic Revatio has been available since early 2013 from makers including Greenstone, Mylan and Watson. Teva sued to invalidate the Viagra patent, but Pfizer won in federal district court in August 2011. Pfizer then settled with both Mylan and Teva, allowing generics in December 2017. In that month Pfizer released its own generic version. By 2018 the FDA had approved fifteen generic manufacturers, seven of them based in India. The erectile dysfunction patent expired in April 2020.

  Elsewhere, the picture varied from country to country. Pfizer's patent on sildenafil citrate expired in Brazil in 2010. In June 2013 it expired in several European Union countries, including Germany, France and Spain. A UK patent on PDE5 inhibitors for impotence was invalidated in 2000 as obvious, and that ruling was upheld on appeal in 2002. Egypt approved Viagra in 2002 but soon let local companies make generics, citing poor people who could not afford Pfizer's price. In China, Pfizer's patent claim is not widely enforced.

  In India, generic versions are common and sold under names such as Kamagra from Ajanta Pharma, Silagra from Cipla, Edegra from Sun Pharmaceutical, Penegra from Zydus Cadila, Manly from Cooper Pharma and Zenegra from Alkem Laboratories.

  South Korea shows how fast generics can move. Pfizer received two patents there in 1999, and in 2011 Hanmi Pharmaceutical and CJ CheilJedang sued against the one covering use for erectile dysfunction. The courts ruled against Pfizer in June 2012. That year Hanmi's PalPal brought in 22 billion won, equal to about 86% of Viagra's market share. By 2017 more than 50 generic sildenafil pills were available, and Viagra sales had slumped to 38% of PalPal's.

  In the United States, Viatris now markets Revatio and Viagra after Upjohn was spun off from Pfizer. In 2023 sildenafil was still the 151st most commonly prescribed medication in the country, with more than 3 million prescriptions.

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