Sildenafil

Sildenafil, sold as the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.[3] It is unclear if it is effective for treating sexual dysfunction in women.[3] It is taken by mouth or injection into a vein.[3] Onset is typically within 20 minutes and lasts for about 2 hours.[3]

Common side effects include headachesheartburn, and flushed skin.[3] Caution is advised in those with cardiovascular disease.[3] Rare but serious side effects include a prolonged erection that can lead to damage to the penis, vision problems, and hearing loss.[3] Sildenafil should not be taken by people on nitrates such as nitroglycerin (glycerin trinitrate), as this may result in a serious drop in blood pressure.[3]

Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis.[3] It requires sexual arousal, however, to work.[3] It also results in dilation of the blood vessels in the lungs.[3]

Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain.[4] It was approved for medical use in the United States and Europe in 1998.[3][4] In the United States, about 2 million prescriptions were written for sildenafil in 2016.[5] In 2017, it became available as a generic medication.[6] In the United Kingdom, it is available over the counter.[7] As of 2018 in the United States, the wholesale cost is less than US$1 per dose.[8]

Medical uses

Pfizer Viagra tablet in the trademark blue diamond shape

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus.[9]

Antidepressant-associated sexual dysfunction

Tentative evidence suggests that sildenafil may help men who experience antidepressant-induced erectile dysfunction.[10]

Pulmonary hypertension

While sildenafil improves some markers of disease in people with pulmonary arterial hypertension, it does not appear to affect the risk of death or serious side effects as of 2014.[11]

Raynaud’s phenomenon

Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud’s phenomenon;[12][13] these drugs have moderate efficacy for reducing the frequency and duration of vasospastic episodes.[12] As of 2016, their role more generally in Raynaud’s was not clear.[13]

High-altitude pulmonary edema

Sildenafil has been studied for high-altitude pulmonary edema, but its use is currently not recommended for that indication.[14]

Adverse effects

In clinical trials, the most common adverse effects of sildenafil use included headacheflushingindigestionnasal congestion, and impaired vision, including photophobia and blurred vision.[2] Some sildenafil users have complained of seeing everything tinted blue (cyanopsia).[15] Some complained of blurriness and loss of peripheral vision. In July 2005, the FDA found that sildenafil could lead to vision impairment in rare cases,[16] and a number of studies have linked sildenafil use with non-arteritic anterior ischemic optic neuropathy.[17]

Rare but serious adverse effects found through postmarketing surveillance include prolonged erections, severe low blood pressuremyocardial infarction (heart attack), ventricular arrhythmiasstroke, increased intraocular pressure, and sudden hearing loss.[2] In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including sildenafil, required a more prominent warning of the potential risk of sudden hearing loss.[18]

Interactions

Care should be exercised by people who are also taking protease inhibitors for the treatment of HIV infection. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side effects. Those using protease inhibitors are recommended to limit their use of sildenafil to no more than one 25 mg dose every 48 hours.[2] Other drugs that interfere with the metabolism of sildenafil include erythromycin and cimetidine, both of which can also lead to prolonged plasma half-life levels.

The use of sildenafil and an α1 blocker (typically prescribed for hypertension or for urologic conditions, such as benign prostatic hypertrophy) at the same time may lead to low blood pressure, but this effect does not occur if they are taken at least 4 hours apart.[19]

Contraindications

Contraindications include:[2]:11

Sildenafil should not be used if sexual activity is inadvisable due to underlying cardiovascular risk factors[21]

Nonmedical use

Recreational use

Sildenafil’s popularity with young adults has increased over the years.[22] Sildenafil’s trade name, Viagra, is widely recognized in popular culture, and the drug’s association with treating erectile dysfunction has led to its recreational use.[23] The reasons behind such use include the belief that the drug increases libido, improves sexual performance,[23] or permanently increases penis size.[24] Studies on the effects of sildenafil when used recreationally are limited, but suggest it has little effect when used by those not suffering from erectile dysfunction. In one study, a 25-mg dose was shown to cause no significant change in erectile quality, but did reduce the postejaculatory refractory time.[25] This study also noted a significant placebo effect in the control group.[25]

Unprescribed recreational use of sildenafil and other PDE5 inhibitors is noted as particularly high among users of illegal drugs.[26] Sildenafil is sometimes used to counteract the effects of other substances, often illicit.[23] Some users mix it with methylenedioxymethamphetamine (MDMA, ecstasy), other stimulants, or opiates in an attempt to compensate for the common side effect of erectile dysfunction, a combination known as “sextasy“, “rockin’ and rollin'” or “trail mix”.[23] Mixing it with amyl nitrite, another vasodilator, is particularly dangerous and potentially fatal.[23]

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 sildenafil helps treat jet lag recovery in hamsters.[27][28]

Sports

Professional athletes have been documented using sildenafil, believing the opening of their blood vessels will enrich their muscles. In turn, they believe it will enhance their performances.[29][30]

Analogs

Acetildenafil and other synthetic structural analogs of sildenafil which are PDE5 inhibitors have been found as adulterants in a number of “herbal” aphrodisiac products sold over-the-counter.[31] These analogs have not undergone any of the rigorous testing that drugs like sildenafil have passed, and thus have unknown side-effect profiles.[32] Some attempts have been made to ban these drugs, but progress has been slow so far, as, even in those jurisdictions that have laws targeting designer drugs, the laws are drafted to ban analogs of illegal drugs of abuse, rather than analogs of prescription medicines. However, at least one court case has resulted in a product being taken off the market.[33]

The US FDA has banned numerous products claiming to be Eurycoma longifolia that, in fact, contain only analogs of sildenafil.[34][35][36] Sellers of such fake herbals typically respond by just changing the names of their products.

Detection in biological fluids

Sildenafil and/or N-desmethylsildenafil, its major active metabolite, may be quantified in plasma, serum, or whole blood to assess pharmacokinetic status in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdose.[37]

Mechanism of action

Crystal structure of human PDE5 with bound sildenafil, PDB entry 1udt[38]

Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosumNitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection.[39] Robert F. FurchgottFerid Murad, and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.

The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphataseRhoAIP3 receptorphospholipase C, and others.[40] Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation.[40]

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.[39] 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 broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4(major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildenafil, which is metabolised further. This metabolite also has an affinity for the PDE receptors, about 40% of that of sildenafil. Thus, the metabolite is responsible for about 20% of sildenafil’s action. Sildenafil is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third.[41]

Route of administration

  • When taken by mouth sildenafil for erectile dysfunction results in an average time to onset of erections of 27 minutes (ranging from 12 to 70 minutes).[42]
  • Under the tongue use of sildenafil for erectile dysfunction results in an average onset of action of 15 minutes and lasting for an average of 40 minutes.[43]

There are also mouth spray preparations of sildenafil for faster onset of action.

Chemical synthesis

The preparation steps for synthesis of sildenafil are:[44]

  1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
  2. Hydrolysis with aqueous sodium hydroxide (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 group
  6. Acylation with 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonation to the chlorosulfonyl derivative
  9. Condensation with 1-methylpiperazine.

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 heart disease). The first clinical trials were conducted in Morriston Hospital in Swansea.[45] Phase I clinical trials under the direction of Ian Osterloh suggested the drug had little effect on angina, but it could induce marked penile erections.[46][47] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina; this decision became an often-cited example of drug repositioning.[48][49] The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on 27 March 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.[50] It soon became a great success: annual sales of Viagra peaked in 2008 at US$1.934 billion.[51]

Marketing and sales

In the US, even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on 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.[52][53] 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”, or “blue diamond”, as well as various other nicknames.

In 2000, Viagra sales accounted for 92% of the global market for prescribed erectile dysfunction pills.[54] By 2007, Viagra’s global share had plunged to about 50%[55] due to several factors, including the entry of Cialis and Levitra, along with several counterfeits and clones, and reports of vision loss in people taking PDE5 inhibitors.[56][57] In 2008, the FDA forced Pfizer to remove Viva Cruiser, an advergame for Viagra, from its website, after the game failed to disclose risk information about the drug.[58][59]

In February 2007, it was announced that Boots, the UK pharmacy chain, would try over-the-counter sales of Viagra in stores in Manchester, England. Men between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.[60] In 2017, the Medicines and Healthcare products Regulatory Agency enacted legislation that expanded this nationwide.,[61] allowing a particular branded formulation of Sildenafil, Viagra Connect (50 mg), to be sold over the counter and without a prescription throughout the UK from early 2018. While the sale remains subject to a consultation with a pharmacist, the other restrictions from the trial have been removed, allowing customers over the age of 18 to purchase an unlimited number of pills [62] The decision was made, in part, to reduce online sales of counterfeit and potentially dangerous erectile dysfunction treatments.

On 6 May 2013, Pfizer, which manufactures Viagra, told The Associated Press they will begin selling the drug directly to patients on its website.[63]

Pfizer’s patents on Viagra expired outside the US in 2012; in the US they were set to expire, but Pfizer settled litigation with each of Mylan and Teva which agreed that both companies could introduce generics in the US on 11 December 2017.[64][65] In December 2017, Pfizer released its own generic version of Viagra.[66][67]

As of 2018, the U.S. Food and Drug Administration has approved 15 drug manufacturers to market generic sildenafil in the United States. Seven of these companies are based in India. This is likely to lead to dramatic price reductions.[68][69]

Counterfeits

Counterfeit Viagra, despite generally being cheaper,[70] can contain harmful substances or substances that affect how Viagra works, such as blue printer ink, amphetaminesmetronidazoleboric acid, and rat poison.[71]

Viagra is one of the world’s most counterfeited medicines.[72][73] According to a Pfizer study, around 80% of sites claiming to sell Viagra were selling counterfeits.[71]

Regional issues

European Union

Pfizer’s patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013.[74][75][76] A 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.[77][78]

United Kingdom

There were 2,958,199 prescriptions for Sildenafil in 2016 in England, compared with 1,042,431 in 2006.[79]

In 2018, Viagra Connect, a particular formulation of Sildenafil marketed by Pfizer, became available for sale without a prescription in the UK,[62] in an attempt to widen availability and reduce demand for counterfeit products.

United States

Sildenafil is available as a generic drug in the United States, labelled for pulmonary arterial hypertension.[80] As of 2016 branded pills cost about 50 times more than generic ones.[80] In the United States as of 2015 the branded 50 mg pill cost is between 25.17 and US$37.88.[81]

In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.[80]

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[82] This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013.[83] Health care providers may prescribe generic sildenafil for erectile dysfunction.[80] However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.[80]

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[84] This would be marketed as Viagra. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.[85] An agreement with Pfizer allowed Teva to begin to provide the generic drug in December 2017.[80]

Canada

In Canada, Pfizer’s patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.[86][87]

On 8 November 2012, the Supreme Court of Canada ruled that Pfizer’s patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information “to enable any person skilled in the art or science to which it pertains” to produce it. It added further: “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.”[88]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[89][90][91] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[92] However, on 9 November 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[93] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[94] Finally, on 22 April 2013, the Supreme Court of Canada invalidated Pfizer’s patent altogether.[95]

India

Manufacture and sale of sildenafil citrate drugs known as “generic Viagra” is common in India, where Pfizer’s patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), Manly (Cooper Pharma) and Zenegra (Alkem Laboratories).

China

Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer’s patent claim is not widely enforced.

New Zealand

Sildenafil was reclassified in New Zealand in 2014 so it could be bought over the counter from a pharmacist. It is thought that this reduced sales over the Internet and was safer as men could be referred for medical advice if appropriate.[96]

Other countries

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer’s price.[97]

Pfizer’s patent on sildenafil citrate expired in Brazil in 2010.[98]

References

  1. ^ Nichols, DJ; Muirhead, GJ; Harness, JA (6 March 2002). “Pharmacokinetics of Sildenafil after Single Oral Doses in Healthy Male Subjects: Absolute Bioavailability, Food Effects and Dose Proportionality”British Journal of Clinical Pharmacology53: 5S–12S. doi:10.1046/j.0306-5251.2001.00027.xPMC 1874258PMID 11879254.
  2. Jump up to:a b c d e “Viagra (sildenafil citrate) Tablets, for Oral Use. Full Prescribing Information”. Pfizer Labs. Division of Pfizer, Inc., NY, NY 10017. Retrieved 5 November 2016.
  3. Jump up to:a b c d e f g h i j k l “Sildenafil Citrate”. The American Society of Health-System Pharmacists. Retrieved 1 December 2014.
  4. Jump up to:a b Goldstein, I; Burnett, AL; Rosen, RC; Park, PW; Stecher, VJ (6 October 2018). “The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction”. Sexual Medicine Reviews7 (1): 115–128. doi:10.1016/j.sxmr.2018.06.005PMID 30301707.
  5. ^ “The Top 300 of 2019”clincalc.com. Retrieved 21 November 2018.
  6. ^ Gordon, Serena (11 December 2017). “Generic Viagra: Two versions of sildenafil hit the market today”CBS News. Retrieved 24 November 2018.
  7. ^ LaMattina, John. “With Viagra Now Available Over-The-Counter In The U.K., Will The U.S. Follow Suit?”Forbes. Retrieved 24 November 2018.
  8. ^ “NADAC as of 2018-11-21”Centers for Medicare and Medicaid Services. Retrieved 24 November 2018.
  9. ^ Vardi, M; Nini, A (24 January 2007). “Phosphodiesterase Inhibitors for Erectile Dysfunction in Patients with Diabetes Mellitus”The Cochrane Database of Systematic Reviews (1): CD002187. doi:10.1002/14651858.CD002187.pub3PMC 6718223PMID 17253475.
  10. ^ Taylor, MJ; Rudkin, L; Bullemor-Day, P; Lubin, J; Chukwujekwu, C; Hawton, K (31 May 2013). “Strategies for Managing Sexual Dysfunction Induced by Antidepressant Medication”The Cochrane Database of Systematic Reviews (5): CD003382. doi:10.1002/14651858.CD003382.pub3PMID 23728643.
  11. ^ Wang, RC; Jiang, FM; Zheng, QL; Li, CT; Peng, XY; He, CY; Luo, J; Liang, ZA (March 2014). “Efficacy and Safety of Sildenafil Treatment in Pulmonary Arterial Hypertension: a Systematic Review”Respiratory Medicine108 (3): 513–17. doi:10.1016/j.rmed.2014.01.003PMID 24462476. Retrieved 5 November 2016.
  12. Jump up to:a b Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski JL (October 2013). “Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials”Annals of the Rheumatic Diseases72 (10): 1696–99. doi:10.1136/annrheumdis-2012-202836PMID 23426043PDE-5 inhibitors appear to have significant but moderate efficacy in secondary [Raynaud’s phenomenon].
  13. Jump up to:a b Linnemann B, Erbe M (2016). “Raynaud’s phenomenon and digital ischaemia – pharmacologic approach and alternative treatment options”. VASA45 (3): 201–12. doi:10.1024/0301-1526/a000526PMID 27129065Phosphodiesterase inhibitors (e.g., sildenafil) can also improve [Raynaud’s phenomenon] symptoms and ulcer healing
  14. ^ Nieto Estrada, Víctor H; Molano Franco, Daniel; Medina, Roger David; Gonzalez Garay, Alejandro G; Martí-Carvajal, Arturo J; Arevalo-Rodriguez, Ingrid (27 June 2017). “Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs”Cochrane Database of Systematic Reviews6: CD009761. doi:10.1002/14651858.CD009761.pub2PMC 6481751PMID 28653390.
  15. ^ “Viagra and Vision”. VisionWeb. 29 October 2001. Retrieved 5 November 2016.
  16. ^ “FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems”U.S. Food and Drug Administration. 8 July 2005. Archived from the original on 22 October 2016. Retrieved 5 November 2016.
  17. ^ Laties, AM (January 2009). “Vision Disorders and Phosphodiesterase Type 5 Inhibitors: a Review of the Evidence to Date”. Drug Safety32 (1): 1–18. doi:10.2165/00002018-200932010-00001PMID 19132801.
  18. ^ “FDA Announces Revisions to Labels for Cialis, Levitra and Viagra”. U.S. Food and Drug Administration. 18 October 2007. Archived from the original on 22 October 2016. Retrieved 5 November 2016.
  19. ^ Kloner, RA (26 December 2005). “Pharmacology and Drug Interaction Effects of the Phosphodiesterase 5 Inhibitors: Focus on α-Blocker Interactions”. The American Journal of Cardiology96 (12 (Suppl. 2)): 42–46. doi:10.1016/j.amjcard.2005.07.011PMID 16387566.
  20. ^ Cheitlin, MD; Hutter, AM Jr; Brindis, RG; Ganz, P; Kaul, S; Russell, RO Jr; Zusman, RM (15 November 1999). “ACC/AHA Expert Consensus Document. Use of Sildenafil (Viagra) in Patients with Cardiovascular Disease”. Journal of the American College of Cardiology34(6): 273–82. doi:10.1016/S0735-1097(98)00656-1PMID 9935041.
  21. ^ “Viagra (Sildenafil Citrate): Side Effects, Interactions, Warning, Dosage & Uses”RxList. Retrieved 11 July 2018.
  22. ^ Peterson K (21 March 2001). “Young men add Viagra to their drug arsenal”USA Today.
  23. Jump up to:a b c d e Smith KM, Romanelli F (2005). “Recreational use and misuse of phosphodiesterase 5 inhibitors”. J Am Pharm Assoc (2003)45 (1): 63–72, quiz 73–75. doi:10.1331/1544345052843165PMID 15730119.
  24. ^ “Sildenafil Will Not Affect Libido – Fact!”. Retrieved 15 July 2016.
  25. Jump up to:a b Mondaini N, Ponchietti R, Muir GH, Montorsi F, Di Loro F, Lombardi G, Rizzo M (June 2003). “Sildenafil does not improve sexual function in men without erectile dysfunction but does reduce the postorgasmic refractory time”. Int. J. Impot. Res15 (3): 225–28. doi:10.1038/sj.ijir.3901005PMID 12904810.
  26. ^ McCambridge J, Mitcheson L, Hunt N, Winstock A (March 2006). “The rise of Viagra among British illicit drug users: 5-year survey data”Drug Alcohol Rev25 (2): 111–13. doi:10.1080/09595230500537167PMID 16627299.
    – Eloi-Stiven ML, Channaveeraiah N, Christos PJ, Finkel M, Reddy R (November 2007). “Does marijuana use play a role in the recreational use of sildenafil?”. J Fam Pract56 (11): E1–4. PMID 17976333.
  27. ^ “The 2007 Ig Nobel Prize Winners”. Improbable Research. 4 October 2007. Retrieved 10 February 2009.
  28. ^ Agostino PV, Plano SA, Golombek DA (June 2007). “Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules”Proc. Natl. Acad. Sci. U.S.A104(23): 9834–39. Bibcode:2007PNAS..104.9834Adoi:10.1073/pnas.0703388104PMC 1887561PMID 17519328.
  29. ^ Teri Thompson; Christian Red; Michael O’Keefffe; Nathaniel Vinton (10 June 2008). “Source: Roger Clemens, host of athletes pop Viagra to help onfield performance”Daily News. Retrieved 10 February 2009.
  30. ^ Busbee J (28 November 2012). “Bears’ Brandon Marshall says some NFL players use Viagra … ON THE FIELD”Yahoo! Sports. Retrieved 28 November 2012.
  31. ^ Venhuis BJ, de Kaste D (2006–2012). “Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: a history, analytical aspects and health risks”. Journal of Pharmaceutical and Biomedical Analysis69: 196–208. doi:10.1016/j.jpba.2012.02.014PMID 22464558.
  32. ^ Oh SS, Zou P, Low MY, Koh HL (2006). “Detection of sildenafil analogues in herbal products for erectile dysfunction”. Journal of Toxicology and Environmental Health Part A69(21): 1951–58. doi:10.1080/15287390600751355PMID 16982533.
  33. ^ Venhuis BJ, Blok-Tip L, de Kaste D (2008). “Designer drugs in herbal aphrodisiacs”. Forensic Science International177 (2–3): 25–27. doi:10.1016/j.forsciint.2007.11.007PMID 18178354.
  34. ^ FDA letter to Libidus distributor
  35. ^ FDA Warns Consumers About Dangerous Ingredients in “Dietary Supplements” Promoted for Sexual Enhancement
  36. ^ Hidden Risks of Erectile Dysfunction “Treatments” Sold Online
  37. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–53. “Archived copy” (PDF). Archived from the original (PDF) on 10 September 2011. Retrieved 1 July 2011.
  38. ^ Sung, B. J.; Hwang, K.; Jeon, Y.; Lee, J. I.; Heo, Y. S.; Kim, J.; Moon, J.; Yoon, J.; Hyun, Y. L.; Kim, E.; Eum, S.; Park, S. Y.; Lee, J. O.; Lee, T.; Ro, S.; Cho, J. (2003). “Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules”. Nature425(6953): 98–102. Bibcode:2003Natur.425…98Sdoi:10.1038/nature01914PMID 12955149.
  39. Jump up to:a b Webb, D.J.; Freestone, S.; Allen, M.J.; Muirhead, G.J. (4 March 1999). “Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist”. Am. J. Cardiol83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2PMID 10078539.
  40. Jump up to:a b Francis, S. H.; Busch, J. L.; Corbin, J. D. (1 September 2010). “cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action”Pharmacological Reviews62 (3): 525–563. doi:10.1124/pr.110.002907ISSN 0031-6997PMC 2964902PMID 20716671.
  41. ^ “Viagra Clinical Pharmacology”. RxList.com. 2008. Retrieved 20 August 2008.
  42. ^ Eardley I, Ellis P, Boolell M, Wulff M (2002). “Onset and duration of action of sildenafil for the treatment of erectile dysfunction”Br J Clin Pharmacol. 53 Suppl 1: 61S–65S. doi:10.1046/j.0306-5251.2001.00034.xPMC 1874251PMID 11879261.
  43. ^ Deveci S, Peşkircioğlu L, Aygün C, Tekin MI, Dirim A, Ozkardeş H (2004). “Sublingual sildenafil in the treatment of erectile dysfunction: faster onset of action with less dose”. Int. J. Urol11 (11): 989–92. doi:10.1111/j.1442-2042.2004.00933.xPMID 15509203.
  44. ^ Dunn PJ (2005). “Synthesis of Commercial Phosphodiesterase(V) Inhibitors”Org Process Res Dev2005 (1): 88–97. doi:10.1021/op040019c.
  45. ^ “Research”ABM. Abertawe Bro Morgannwg University Health Board. 4 July 2008. Archived from the original on 26 September 2008. Retrieved 6 August 2008Our clinicians regularly offer patients the opportunity to take part in trials of new drugs and treatments. Morriston Hospital in Swansea, was the first in the world to trial Viagra!
  46. ^ Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (June 1996). “Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction”. Int. J. Impot. Res8 (2): 47–52. PMID 8858389.
  47. ^ Terrett NK, Bell AS, Brown D, Elllis P (1996). “Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction”. Bioorg Med Chem Lett6 (15): 1819–24. doi:10.1016/0960-894X(96)00323-X.
  48. ^ Ashburn, TT; Thor, KB (August 2004). “Drug repositioning: identifying and developing new uses for existing drugs”. Nature Reviews. Drug Discovery3 (8): 673–83. doi:10.1038/nrd1468PMID 15286734.
  49. ^ Institute of Medicine (2014). Drug Repurposing and Repositioning: Workshop Summary. National Academies Press. ISBN 9780309302043.
  50. ^ Kling J (1998). “From hypertension to angina to Viagra”. Mod. Drug Discov1: 31–38. ISSN 1532-4486OCLC 41105083.
  51. ^ “Portions of the 2010 Financial Report”. Retrieved 15 July 2016.
  52. ^ Ciment, J (1999). “Missouri fines internet pharmacy”BMJ319 (7221): 1324. doi:10.1136/bmj.319.7221.1324gPMC 1174637PMID 10567131.
  53. ^ Devine, Amy (29 September 2008). “Chemists plan to sell Viagra on the internet”Daily Record. Retrieved 30 April 2012.
  54. ^ Keith A (2000). “The economics of Viagra”. Health Aff (Millwood)19 (2): 147–57. doi:10.1377/hlthaff.19.2.147PMID 10718028.
  55. ^ McGuire S (1 January 2007). “Cialis gaining market share worldwide”Medical Marketing & Media. Haymarket Media. Archived from the original on 3 January 2009. Retrieved 10 February 2009.
  56. ^ Mullin, Rick (20 June 2005). “Viagra”Chemical & Engineering News83 (25). Retrieved 20 August 2008.
  57. ^ Berenson, Alex (4 December 2005). “Sales of Impotence Drugs Fall, Defying Expectations”The New York Times. Retrieved 20 August 2008.
  58. ^ “Pfizer Courting More Controversy with Viagra ‘Advergamingwww.cbsnews.com. Retrieved 19 December 2019.
  59. ^ “FDA gave Pfizer hard time over Viagra game”Engadget. Retrieved 19 December2019.
  60. ^ “Over-the-counter Viagra piloted”BBC News. 11 February 2007. Retrieved 10 February2009.
  61. ^ “Viagra can be sold over the counter”BBC News. 28 November 2017. Retrieved 5 April2018.
  62. Jump up to:a b “Viagra now available over the counter without prescription in the UK”The Independent. 27 March 2018. Retrieved 5 April 2018.
  63. ^ “Pfizer to sell Viagra online, in first for Big Pharma: AP”. CBS News. Retrieved 6 May2013.
  64. ^ Helfand, Carly (14 April 2015). “The coming generics threat to Pfizer’s Viagra brand just got scarier”FiercePharma.
  65. ^ “Viagra to go generic in 2017 according to Pfizer agreement”. CBS News. 17 December 2013.
  66. ^ Nocera, Joe (6 December 2017). “Sex, Drugs and That Little Blue Pill”. Bloomberg. Retrieved 10 December 2017.
  67. ^ Mukherjee, Sy (6 December 2017). “Why Pfizer Is About to Slash Viagra’s Price in Half”Fortune. Retrieved 6 December 2017.
  68. ^ Chandna, Himani (7 August 2018). “Pfizer to lose patent of drug Viagra, Indian companies gear up with copycat versions: Pfizer’s patent for the formulation of Viagra, used to treat impotence in men, ends in the US in 2020”Hindustan TimesNew Delhi. Retrieved 10 August 2018.
  69. ^ “Set to conquer US, Indian ‘Viagras’ may give Pfizer a hard Time”The Economic TimesMumbai. 3 August 2018. Retrieved 10 August 2010.
  70. ^ “Record amount of counterfeit Viagra seized”www.bbc.com. 12 May 2016. Archivedfrom the original on 19 November 2016. Retrieved 26 December 2016.
  71. Jump up to:a b Amerman, Don (22 May 2012). “Counterfeit Viagra, Cialis, Levitra: The Ultimate Guide”AccessRx. Retrieved 10 January 2017.
  72. ^ Moran, Barbara (20 August 2013). “Cracking Down on Counterfeit Drugs — NOVA Next | PBS”. PBS NOVA Next. Retrieved 10 January 2017.
  73. ^ CNN, Gena Somra (31 August 2015). “Online pharmacies suspected of counterfeit drug sales”. CNN. Retrieved 10 January 2017.
  74. ^ “Actavis Launches Generic Viagra in Europe as Patents Expire”. Retrieved 25 October2013.
  75. ^ Jim Edwards (21 October 2009). “What Will Happen When Viagra Goes Generic?”. AccessRx.com. Retrieved 25 March 2011.
  76. ^ “Is Viagra about to lose its pulling power in the UK?”The Guardian. 3 June 2013. Retrieved 13 June 2013.
  77. ^ Murray-, Rosie (23 January 2002). “Viagra ruling upsets Pfizer”. London: Telegraph Media Group Limited. Archived from the original on 22 August 2009. Retrieved 10 February 2009.
  78. ^ “Pfizer Loses UK Battle on Viagra Patent”UroToday. Thomson Reuters. 17 June 2002. Archived from the original on 25 June 2007. Retrieved 10 February 2009.
  79. ^ “Viagra prescriptions almost triple in a decade”. Pharmaceutical Journal. 21 August 2017. Retrieved 8 October 2017.
  80. Jump up to:a b c d e f Skinner, Ginger (4 March 2016). “Yes, There Is a Way to Get Generic Viagra”Consumer Reports. Retrieved 4 May 2016.
  81. ^ Langreth, Robert (29 June 2016). “Decoding Big Pharma’s Secret Drug Pricing Practices”. Bloomberg. Retrieved 15 July 2016.
  82. ^ U.S. Patent 5,250,534
  83. ^ “Pfizer’s Revatio Goes Generic”. Zacks Equity Research. 15 November 2012. Retrieved 5 October 2013.
  84. ^ U.S. Patent 6,469,012
  85. ^ “Pfizer Wins Viagra Patent Infringement Case Against Teva Pharmaceuticals”. Bloomberg. 15 August 2011. Retrieved 1 April 2012.
  86. ^ “Revation patent ruled invalid for lack of sound prediction and obviousness”Canadian Technology & IP Law. Stikeman Elliott. 18 June 2010. Retrieved 14 November 2012.
  87. ^ Pfizer Canada Inc. v. Ratiopharm Inc., 2010 FC 612″. CanLII.
  88. ^ Teva Canada Ltd. v. Pfizer Canada Inc. 2012 SCC 60 at par. 80 (8 November 2012)
  89. ^ John Spears (8 November 2012). “Supreme Court ruling could lead to cheaper versions of Viagra”Toronto Star. Retrieved 14 November 2012.
  90. ^ Ken Hanly (8 November 2012). “Canadian Supreme court rules Viagra patent invalid”Digital Journal. Retrieved 14 November 2012.
  91. ^ “Viagra patent tossed out by Supreme Court: Decision allows generic versions of drug to be produced”CBC News. 8 November 2012. Retrieved 14 November 2012.
  92. ^ “Pfizer Canada drops Viagra price after generic versions get Supreme Court green light”Financial Post. 22 November 2012. Retrieved 9 February 2013.
  93. ^ “SCC Case Information, Docket No. 33951”. January 2001. Retrieved 14 November2012.
  94. ^ Kirk Makin (15 November 2012). “In rare move, Pfizer asks Supreme Court to reconsider ruling that killed Viagra patent”The Globe and Mail. Retrieved 15 November 2012.
  95. ^ Gowling Lafleur Henderson LLP; Hélène D’Iorio (22 April 2013). “The Supreme Court of Canada holds Pfizer’s Viagra patent invalid”Lexology. Retrieved 27 December 2013.
  96. ^ “Viagra from the pharmacist: insight from reclassification in New Zealand”. Pharmaceutical Journal. 31 January 2018. Retrieved 2 April 2018.
  97. ^ Allam, Abeer (4 October 2002). “Seeking Investment, Egypt Tries Patent Laws”New York Times. Retrieved 1 April 2013.
  98. ^ in-PharmaTechnologist.com. “Viagra patent expires in June, says Brazilian court”. Retrieved 15 July 2016.

Marketing

n the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers.[24] Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the Grey Global Group, to run the Cialis advertising campaign.[25] Marketers for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug; Stuart Elliot of The New York Times opined: “The continuous presence of women in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with their men, in contrast to the primarily male-driven imagery for Levitra and Viagra.”[25] Iconic themes in Cialis ads include couples in bathtubs and the slogan “When the moment is right, will you be ready?”[25] Cialis ads were unique among the ED drugs in mentioning specifics of the drug.[26] As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 Super Bowl.[26] Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism.[26] Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson‘s halftime “wardrobe malfunction” overshadowed Cialis.[26] In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads.[24] In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively.[26] Cialis has sponsored many sporting events, including the America’s Cup and the PGA Tour, once being title sponsor of the PGA Tour Western Open tournament.[27]

Cost[edit]

In the United States, the wholesale cost of tadalafil as of May 2019 is US$1.91 for the 20 mg tabs and US$7.65 for the 2.5 mg tabs.[4]

While some health insurance providers cover at least part of the cost (typically limiting the number of doses covered per month), many providers, including those operating under Medicare Part D, do not cover the cost of medications prescribed for erectile dysfunction.[28][29]

In the U.K., a generic version of tadalafil became available in November 2017, reducing its price per pill, and will be available on the NHS. Additionally, Tadacip, manufactured in India by Cipla, is considerably less expensive.

References[edit]

  1. ^ “Cialis (tadalafil) Tablets, for Oral Use. Full Prescribing Information”. Lilly USA, LLC. Indianapolis, IN 46285, USA. Retrieved 5 November 2016.
  2. Jump up to:a b c d e f g h i j k “Tadalafil Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 8 April 2019.
  3. Jump up to:a b British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 796. ISBN 9780857113382.
  4. Jump up to:a b “NADAC as of 2019-05-15”Centers for Medicare and Medicaid Services. Retrieved 29 May 2019.
  5. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December 2018.
  6. ^ “Pill Splitting” (PDF). Consumer Reports Health. 2010-01-25. Archived from the original (PDF) on 2008-10-08.
  7. ^ Wang Y, Bao Y, Liu J, Duan L, Cui Y (January 2018). “Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta-analysis”. Low Urin Tract Symptoms10 (1): 84–92. doi:10.1111/luts.12144PMID 29341503.
  8. ^ Penedones A, Alves C, Batel Marques F (2020). “Risk of nonarteritic ischaemic optic neuropathy with phosphodiesterase type 5 inhibitors: a systematic review and meta-analysis”. Acta Ophthalmol98 (1): 22–31. doi:10.1111/aos.14253PMID 31559705.
  9. ^ “FDA Announces Revisions to Labels for Cialis, Levitra and Viagra”Food and Drug Administration. 2007-10-18. Archived from the original on 2016-10-22. Retrieved 2009-09-28.
  10. ^ Sriram D. Medicinal Chemistry. Pearson Education India, 2010. p. 635.
  11. ^ Kaye K. Gaines. “Tadalafil (Cialis) and Vardenafil (Levitra) Recently Approved Drugs for Erectile Dysfunction”. Medscape.
  12. Jump up to:a b c d e f g Bischoff, E (June 2004). “Potency, selectivity, and consequences of nonselectivity of PDE inhibition”. International Journal of Impotence Research16: S11–4. doi:10.1038/sj.ijir.3901208PMID 15224129.
  13. Jump up to:a b Ervin, Keith (June 21, 1998). “Deep Pockets + Intense Research + Total Control = The Formula — Bothell Biotech Icos Keeps The Pipeline Full Of Promise”The Seattle Times. p. F1. Retrieved January 10, 2009.
  14. ^ Borthwick AD (May 2012). “2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products”. Chemical Reviews112 (7): 3641–3716. doi:10.1021/cr200398yPMID 22575049.
  15. ^ Baumann M (May 2011). “An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals”Beilstein Journal of Organic Chemistry7: 442–495. doi:10.3762/BJOC.7.57PMC 3107522PMID 21647262.
  16. ^ “FDA approves Viagra”. History.com. Retrieved 2014-11-12.
  17. ^ “Generic Levitra Availability”. Drugs.com. Retrieved 2015-06-01.
  18. ^ “FDA approves tadalafil for pulmonary arterial hypertension”. Drugs.com. Retrieved 2014-11-13.
  19. ^ Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Kirilovsky J, Hyafil F, Labaudinière R (October 9, 2003). “The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues”Journal of Medicinal Chemistry46 (21): 4525–32. doi:10.1021/jm030056ePMID 14521414.
  20. ^ Richards, Rhonda (September 17, 1991). “ICOS At A Crest On Roller Coaster”. USA Today. p. 3B.
  21. ^ “Tadalafil”. Drugs.com. Retrieved February 23, 2018.
  22. ^ Revill, Jo (February 2, 2003). “Drugs giant says its new pill will pack more punch than rival Viagra”The Observer. Retrieved 2007-04-06.
  23. ^ “FDA approves Cialis to treat benign prostatic hyperplasia”. U.S. Food and Drug Administration. 2011-10-06. Archived from the original on 2017-01-18.
  24. Jump up to:a b Elliott, Stuart (January 10, 2006). “For Impotence Drugs, Less Wink-Wink”The New York Times. p. C2. Retrieved April 22, 2018.
  25. Jump up to:a b c Elliott, Stuart (April 25, 2004). “Viagra and the Battle of the Awkward Ads”. Business Day. The New York Times. p. 1. Retrieved April 22, 2018.
  26. Jump up to:a b c d e McCarthy, Shawn (March 5, 2005). “First they tried to play it safe; Ads for erectile dysfunction drug Cialis bared all – including a scary potential side effect. It was risky but it has paid off”The Globe and Mail. p. B4.
  27. ^ Loyd, Linda (July 6, 2003). “Two Pills Look to Topple Viagra’s Reign in Market; Levitra Expects Approval Next Month, Cialis Later This Year”. The Philadelphia Inquirer. p. E01.
  28. ^ Parker-Pope, Tara (August 28, 2009). “The Cost of Treating Erectile Dysfunction”New York Times. Retrieved 20 Dec 2016.
  29. ^ United Health Care (August 16, 2016). “Coverage Summary — Impotence Treatment”(PDF). United Health Care. Retrieved 20 Dec 2016.

Tadalafil

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.[2] It is a tablet taken by mouth.[2] Onset is typically within half an hour and the duration is up to 36 hours.[2]

Common side effects include headache, muscle pain, flushed skin, and nausea.[2] Caution is advised in those with cardiovascular disease.[2] Rare but serious side effects include a prolonged erection that can lead to damage to the penis, vision problems, and hearing loss.[2] Tadalafil is not recommended in people taking nitrovasodilators such as nitroglycerin, as this may result in a serious drop in blood pressure.[2] Tadalafil is a PDE5 inhibitor which increases blood flow to the penis with sexual arousal.[2] It also dilates blood vessels in the lungs, which lowers the pulmonary artery pressure.[2]

Tadalafil was approved for medical use in the United States in 2003.[2] It is available as a generic medication in the United States and United Kingdom.[3] In the UK it costs the NHS about 0.80 £ per dose as of 2019.[3] In the United States the wholesale cost of this amount is about US$1.91.[4] In 2016 it was the 280th most prescribed medication in the United States with nearly 1.5 million prescriptions.[5]

Contents
1 Medical uses
1.1 Erectile dysfunction
1.2 Benign prostatic hypertrophy
1.3 Pulmonary arterial hypertension
2 Adverse effects
2.1 Vision
2.2 Hearing
3 Metabolism
4 Mechanism of action
4.1 Duration of action
4.2 Comparison with actions of other PDE5 inhibitors
5 Chemistry
6 History
7 Society and culture
7.1 Marketing
7.2 Cost
8 References
9 External links
Medical uses

20 mg Cialis tablet
Tadalafil is used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.[2]

Erectile dysfunction
Tadalafil once-daily is FDA-approved for ED, for sale in 2.5, 5, 10, and 20 mg strengths. The price of the 5 mg and 2.5 mg are often similar, so some people score and split the pill.[6]

Benign prostatic hypertrophy
A meta‐analysis found that tadalafil 5 mg once‐daily is an effective treatment for lower urinary tract symptoms due to prostatic hyperplasia and that such treatment had a low rate of adverse effects.[7] Tadalafil 10 mg is FDA-approved for men as a once-daily therapy to treat and prevent symptoms of benign prostatic hypertrophy (BPH), such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence.

Pulmonary arterial hypertension
Tadalafil 40 mg is approved in the United States, Canada, and Japan as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension (PAH).

The pulmonary vascular lumen is decreased in PAH as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil causes pulmonary artery vasodilation, and inhibits vascular remodeling, thus lowering pulmonary arterial pressure and resistance. Right heart failure is the principal consequence of severe pulmonary arterial hypertension.
Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.[2] It is a tablet taken by mouth.[2] Onset is typically within half an hour and the duration is up to 36 hours.[2]

Common side effects include headache, muscle pain, flushed skin, and nausea.[2] Caution is advised in those with cardiovascular disease.[2] Rare but serious side effects include a prolonged erection that can lead to damage to the penis, vision problems, and hearing loss.[2] Tadalafil is not recommended in people taking nitrovasodilators such as nitroglycerin, as this may result in a serious drop in blood pressure.[2] Tadalafil is a PDE5 inhibitor which increases blood flow to the penis with sexual arousal.[2] It also dilates blood vessels in the lungs, which lowers the pulmonary artery pressure.[2]

Tadalafil was approved for medical use in the United States in 2003.[2] It is available as a generic medication in the United States and United Kingdom.[3] In the UK it costs the NHS about 0.80 £ per dose as of 2019.[3] In the United States the wholesale cost of this amount is about US$1.91.[4] In 2016 it was the 280th most prescribed medication in the United States with nearly 1.5 million prescriptions.[5]

Contents
1 Medical uses
1.1 Erectile dysfunction
1.2 Benign prostatic hypertrophy
1.3 Pulmonary arterial hypertension
2 Adverse effects
2.1 Vision
2.2 Hearing
3 Metabolism
4 Mechanism of action
4.1 Duration of action
4.2 Comparison with actions of other PDE5 inhibitors
5 Chemistry
6 History
7 Society and culture
7.1 Marketing
7.2 Cost
8 References
9 External links
Medical uses

20 mg Cialis tablet
Tadalafil is used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.[2]

Erectile dysfunction
Tadalafil once-daily is FDA-approved for ED, for sale in 2.5, 5, 10, and 20 mg strengths. The price of the 5 mg and 2.5 mg are often similar, so some people score and split the pill.[6]

Benign prostatic hypertrophy
A meta‐analysis found that tadalafil 5 mg once‐daily is an effective treatment for lower urinary tract symptoms due to prostatic hyperplasia and that such treatment had a low rate of adverse effects.[7] Tadalafil 10 mg is FDA-approved for men as a once-daily therapy to treat and prevent symptoms of benign prostatic hypertrophy (BPH), such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence.

Pulmonary arterial hypertension
Tadalafil 40 mg is approved in the United States, Canada, and Japan as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension (PAH).

The pulmonary vascular lumen is decreased in PAH as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil causes pulmonary artery vasodilation, and inhibits vascular remodeling, thus lowering pulmonary arterial pressure and resistance. Right heart failure is the principal consequence of severe pulmonary arterial hypertension.

Adverse effects
The most common potential side effects when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, acid reflux, back pain, muscle aches, flushing, and stuffy and runny nose. These side effects reflect the ability of PDE5 inhibition to cause vasodilation (cause blood vessels to widen), and usually resolve after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and these symptoms usually resolve within 48 hours of onset.

Vision
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy). Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, unrelated to PDE5 use. The FDA concluded that they were not able to draw a cause and effect relationship, only an association; the label of all three PDE5 inhibitors was changed to alert clinicians to that fact. A 2019 meta-analysis found that tadalafil exposure was not associated with NAION.[8]
Adverse effects
The most common potential side effects when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, acid reflux, back pain, muscle aches, flushing, and stuffy and runny nose. These side effects reflect the ability of PDE5 inhibition to cause vasodilation (cause blood vessels to widen), and usually resolve after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and these symptoms usually resolve within 48 hours of onset.

Vision
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy). Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, unrelated to PDE5 use. The FDA concluded that they were not able to draw a cause and effect relationship, only an association; the label of all three PDE5 inhibitors was changed to alert clinicians to that fact. A 2019 meta-analysis found that tadalafil exposure was not associated with NAION.[8]

Metabolism

Tadalafil is metabolized predominantly by the hepatic CYP3A4 enzyme system. The presence of other drugs which induce this system can shorten tadalafil half-life and reduce serum levels, and hence efficacy, of the drug.

Mechanism of action[edit]

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the corpus cavernosum. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic guanosine monophosphate (more commonly known as cyclic GMP or cGMP) in smooth muscle cells. cGMP relaxes smooth muscle and increases blood flow to the corpus cavernosum.

The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5. However, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil’s inhibition of PDE5 will have no effect without direct sexual stimulation of the penis.

Duration of action[edit]

Although sildenafilvardenafil, and tadalafil all work by inhibiting PDE5, tadalafil’s pharmacologic distinction is its longer half-life (17.5 hours),[10] compared to sildenafil and vardenafil, which are both 4–5 hours.[11] This translates to a longer duration of action, which is partly responsible for “The Weekend Pill” nickname. Furthermore, the longer half-life is the basis for tadalafil’s daily therapeutic use in treating pulmonary arterial hypertension.

Comparison with actions of other PDE5 inhibitors[edit]

Tadalafil, sildenafil, and vardenafil all act by inhibiting the PDE5 enzyme, but these drugs also inhibit PDE enzymes 6, 1, and 11 in varying degrees.

Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil.[12] Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.[13]

Sildenafil and vardenafil also inhibit PDE1 more than tadalafil.[12] PDE1 is found in the brain, heart, and vascular smooth muscle.[12] It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilationflushing, and tachycardia.[12]

Tadalafil inhibits PDE11 more than sildenafil or vardenafil.[12] PDE11 is expressed in skeletal muscle, the prostate, the liver, the kidney, the pituitary gland, and the testes.[12] The effects on the body of inhibiting PDE11 are not known.[12]

Chemistry[edit]

Tadalafil is an annulated 2,5-diketopiperazine.[14] It is also a 1,2,3,4-tetrahydro-β-carboline.

Tadalafil can be synthesized starting from (D)-tryptophan methyl ester and piperonal via a Pictet–Spengler reaction. This is followed by condensations with chloroacetyl chloride and methylamine to complete the diketopiperazine ring:[15]

Tadalafil synthesis

History[edit]

The FDA’s approval of sildenafil in 1998[16] was a ground-breaking commercial event for the treatment of ED, with sales exceeding US$1 billion. Subsequently, the FDA approved vardenafil in 2003,[17] and tadalafil in 2003.

It initially was developed by the biotechnology company ICOS, and then again developed and marketed worldwide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Tadalafil was approved in 2009 in the United States for the treatment of pulmonary arterial hypertension[18] and is under regulatory review in other regions for this condition. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for pulmonary arterial hypertension in the United States to United Therapeutics for an upfront payment of $150 million.

Tadalafil was discovered by Glaxo Wellcome (now GlaxoSmithKline) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991.[19][20] In 1993, the Bothell, Washington biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5 (PDE5) enzyme inhibitor. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug’s FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company’s core markets.[13] In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a new drug application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the American Urological Association that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour half-life (thus Cialis is advertised to work for up to 36 hours,[21] after which time there remains approximately 25% of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra).

In 2007, Eli Lilly and Company bought the ICOS Corporation for $2.3 billion. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS’s approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S (CMC).

Persons surnamed “Cialis” objected to Eli Lilly and Company’s so naming the drug, but the company has maintained that the drug’s trade name is unrelated to the surname.[22]

On October 6, 2011, the U.S. FDA approved tadalafil[23] to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in males in which the prostate gland becomes enlarged, obstructing the free flow of urine. Symptoms may include sudden urges to urinate (urgency), difficulty in starting urination (hesitancy), a weak urine stream, and more frequent urination — especially at night. The FDA has also approved tadalafil for treatment of both BPH and erectile dysfunction (ED) where the two conditions co-exist.