Tadalafil

Effects

Overview

Tadalafil, a PDE5 inhibitor used to combat erectile disfunction. Dangerous in combination with other drugs which lower blood pressure. TS

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.[1][2][3] WP

Common side effects include headache, muscle pain, flushing, and nausea. Caution is advised in those with cardiovascular disease. Rare but serious side effects include a prolonged erection that can lead to damage to the penis, vision problems, and hearing loss. Tadalafil is not recommended in people taking nitrovasodilators such as nitroglycerin, as this may result in a serious drop in blood pressure. Tadalafil is a PDE5 inhibitor which increases blood flow to the penis. It also dilates blood vessels in the lungs, which lowers the pulmonary artery pressure.[3] WP

Tadalafil was approved for medical use in the United States in 2003. It is available as a generic medication. In 2022, it was the 172nd most commonly prescribed medication in the United States, with more than 3 million prescriptions.[3–6] WP

History

History

The FDA's approval of sildenafil in 1998 was a ground-breaking commercial event for the treatment of ED, with sales exceeding US$1 billion. Subsequently, the FDA approved both vardenafil and tadalafil in 2003.[7][8] WP

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 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.[9] WP

Tadalafil was discovered by Glaxo Wellcome (now GlaxoSmithKline) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. 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 males 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 males 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. In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, a 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, 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).[10–13] WP

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). WP

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.[14] WP

In October 2011, the US FDA approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia. Benign prostatic hyperplasia is a condition 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 the treatment of both benign prostatic hyperplasia and erectile dysfunction where the two conditions co-exist.[15] WP

Legal status

Marketing

In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers. Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the Grey Global Group, to run the Cialis advertising campaign. Marketing 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 females in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with males, in contrast to the primarily male-driven imagery for Levitra and Viagra." Iconic themes in Cialis ads include couples side by side in matching bathtubs and the slogan "When the moment is right, will you be ready?" Cialis ads were unique among the ED drugs in mentioning specifics of the drug. 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. Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism. Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson's halftime "wardrobe malfunction" overshadowed Cialis. 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. In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively. 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.[16–19] WP

Economics

In Australia, tadalafil is subsidized through the Repatriation Pharmaceutical Benefits Scheme (RPBS) for patients with a specific accepted war- or service-related disability.[20] WP

In the US, a generic version of tadalafil is available. 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.[21][22][23] WP

In the UK, a generic version of tadalafil became available in November 2017, reducing its price per pill, and is available through the NHS. In China, CMOAPI is the largest manufacturer of Tadalafil powder.[24] WP⚠ Wikipedia itself has flagged this text: citation needed.

Pharmacology

Mechanism of action

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. WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

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 sexual stimulation.[25] WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

Duration of action

Although sildenafil, vardenafil, and tadalafil all work by inhibiting PDE5, tadalafil's pharmacologic distinction is its longer half-life (17.5 hours), compared to sildenafil and vardenafil, which are both 4–5 hours. 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.[26][27] WP

Comparison with actions of other PDE5 inhibitors

Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil. Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.[12][28] WP

Sildenafil and vardenafil also inhibit PDE1 more than tadalafil. PDE1 is found in the brain, heart, and vascular smooth muscle. It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation, flushing, and tachycardia.[28] WP

Tadalafil inhibits PDE11 more than sildenafil or vardenafil. PDE11 is expressed in skeletal muscle, the prostate, the liver, the kidney, the pituitary gland, and the testes. The effects on the body of inhibiting PDE11 are not known.[28] WP

Chemistry

Formula

C22H19N3O4 PC

CAS number

171596-29-5 PC

Molar mass (g/mol)

389.4 PC

IUPAC name (computed by PubChem)

(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione PC

SMILES

CN1CC(=O)N2[C@@H](C1=O)CC3=C([C@H]2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36 PC

InChIKey

WOXKDUGGOYFFRN-IIBYNOLFSA-N PC

PubChem CID

110635

Pop culture

No references added yet.

References

1. Journal / agency Cialis- tadalafil tablet, film coated. 12 June 2020
2. Journal / agency Adcirca- tadalafil tablet. 23 June 2022
3. Other Tadalafil Monograph for Professionals
4. Other British national formulary: BNF 76. 2018
5. Other The Top 300 of 2022
6. Other Tadalafil Drug Usage Statistics, United States, 2013 - 2022
7. Other FDA approves Viagra
8. Other Generic Levitra Availability
9. Other FDA approves tadalafil for pulmonary arterial hypertension
10. Journal / agency Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. Journal of Medicinal Chemistry. October 2003. doi:10.1021/jm030056e · PMID 14521415
11. Other Richards R. ICOS At A Crest On Roller Coaster. 17 September 1991
12. Other Ervin K. Deep Pockets + Intense Research + Total Control = The Formula -- Bothell Biotech Icos Keeps The Pipeline Full Of Promise. 21 June 1998
13. Other Tadalafil
14. Other Revill J. Drugs giant says its new pill will pack more punch than rival Viagra. 2 February 2003
15. Journal / agency FDA approves Cialis to treat benign prostatic hyperplasia. 6 October 2011
16. Other Elliott S. For Impotence Drugs, Less Wink-Wink. 10 January 2006
17. Other Elliott S. Viagra and the Battle of the Awkward Ads. 25 April 2004
18. Other McCarthy S. 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. 5 March 2005
19. Other Loyd L. Two Pills Look to Topple Viagra's Reign in Market; Levitra Expects Approval Next Month, Cialis Later This Year. 6 July 2003
20. Other Tadalafil
21. Other Generic Cialis
22. Other Parker-Pope T. The Cost of Treating Erectile Dysfunction. 28 August 2009
23. Other Coverage Summary -- Impotence Treatment. 16 August 2016
24. Other Tadalafil powder & Intermediate
25. Other Cialis tadalafil PI
26. Other Sriram D. Medicinal Chemistry
27. Other Kaye K. Gaines. Tadalafil (Cialis) and Vardenafil (Levitra) Recently Approved Drugs for Erectile Dysfunction
28. Journal / agency Bischoff E. Potency, selectivity, and consequences of nonselectivity of PDE inhibition. International Journal of Impotence Research. June 2004. doi:10.1038/sj.ijir.3901208 · PMID 15224129

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