Tadalafil

Last updated

Tadalafil
Tadalafil.svg
Tadalafil 3D 1XOZ.png
Clinical data
Pronunciation /təˈdæləfɪl/ tə-DAL-ə-fil
Trade names Cialis, Adcirca, others
AHFS/Drugs.com Monograph
MedlinePlus a604008
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class PDE5 inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Varies
Protein binding 94%
Metabolism Liver (predominantly CYP3A4)
Metabolites Catechol metabolite
Onset of action 30 minutes
Elimination half-life 17.5 hours
Duration of action ≤ 36 hours
Excretion Feces (~61%), urine (~36%) [5]
Identifiers
  • (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]
    pyrido[3,4-b]indole-1,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.214.024 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H19N3O4
Molar mass 389.411 g·mol−1
3D model (JSmol)
  • CN1CC(=O)N2[C@H](Cc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)OCO3)C1=O
  • InChI=1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1 Yes check.svgY
  • Key:WOXKDUGGOYFFRN-IIBYNOLFSA-N Yes check.svgY
   (verify)
Tadalafil - STADA T20 - 20 Milligram Tadalafil von STADA - T20 - 20 Milligramm - Potenzmittel - Bild 003.jpg
Tadalafil - STADA T20 - 20 Milligram

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. [5] [6] [8] It is taken by mouth. [8] Onset is typically within half an hour and the duration is up to 36 hours. [8]

Contents

Common side effects include headache, muscle pain, flushed skin, and nausea. [8] Caution is advised in those with cardiovascular disease. [8] Rare but serious side effects include a prolonged erection that can lead to damage to the penis, vision problems, and hearing loss. [8] Tadalafil is not recommended in people taking nitrovasodilators such as nitroglycerin, as this may result in a serious drop in blood pressure. [8] Tadalafil is a PDE5 inhibitor which increases blood flow to the penis. [8] It also dilates blood vessels in the lungs, which lowers the pulmonary artery pressure. [8]

Tadalafil was approved for medical use in the United States in 2003. [8] It is available as a generic medication. [9] In 2022, it was the 172nd most commonly prescribed medication in the United States, with more than 3 million prescriptions. [10] [11]

Medical uses

20 mg Cialis tablet Tadalafil 20mg.jpg
20 mg Cialis tablet

Tadalafil is used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. [8] In the US, tadalafil (as Cialis) is indicated for the treatment of erectile dysfunction and the signs and symptoms of benign prostatic hyperplasia; [5] and (as Adcirca) for the treatment of pulmonary arterial hypertension to improve exercise ability. [6]

Benign prostatic hyperplasia

A meta‐analysis found that tadalafil is an effective treatment for lower urinary tract symptoms due to benign prostatic hyperplasia and that such treatment had a low rate of adverse effects. [12] Tadalafil is FDA-approved for males as a therapy to treat and prevent symptoms of benign prostatic hyperplasia, such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence. Tadalafil was found to have similar benefits for lower urinary tract symptoms as the usually prescribed tamsulosin. [13]

Pulmonary arterial hypertension

Tadalafil is approved in the United States, Canada, and Japan to improve exercise ability in people with pulmonary arterial hypertension. [14] [15]

Adverse effects

The most common potential side effects when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, acid reflux, back pain, myalgia (pain in limbs and extremities), flushing, hypertension (or uncommonly hypotension), and stuffy/runny nose. [8] Also common are dizziness, peripheral edema, fatigue, and urinary or respiratory tract infection; both diarrhea and constipation have been reported. [8] Diarrhea was reported more frequently in patients 65 or older than in younger subjects. [5] These side effects reflect the ability of PDE5 inhibition to cause vasodilation (causing blood vessels to widen) and usually resolve after a few hours. [16]

Vision

In May 2005, the US Food and Drug Administration (FDA) found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy). [17] Most, but not all, of these patients, had underlying anatomic or vascular risk factors for the development of NAION, unrelated to PDE5 inhibitor use. [8] 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. [18]

Hearing

In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including tadalafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of post-marketing reports of temporary deafness associated with use of PDE5 inhibitors. [19]

Metabolism

Tadalafil is metabolized predominantly [20] by the liver CYP3A4 enzyme system.

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.[ medical citation needed ] 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.[ medical citation needed ] cGMP relaxes smooth muscle and increases blood flow to the corpus cavernosum.[ medical citation needed ]

The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP.[ medical citation needed ] 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. [2]

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), [21] compared to sildenafil and vardenafil, which are both 4–5 hours. [22] 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

Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil. [23] Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition. [24]

Sildenafil and vardenafil also inhibit PDE1 more than tadalafil. [23] PDE1 is found in the brain, heart, and vascular smooth muscle. [23] It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation, flushing, and tachycardia. [23]

Tadalafil inhibits PDE11 more than sildenafil or vardenafil. [23] PDE11 is expressed in skeletal muscle, the prostate, the liver, the kidney, the pituitary gland, and the testes. [23] The effects on the body of inhibiting PDE11 are not known. [23]

Chemistry

Tadalafil is an annulated 2,5-diketopiperazine. [25] 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: [26]

Tadalafil synthesis.svg

History

The FDA's approval of sildenafil in 1998 [27] was a ground-breaking commercial event for the treatment of ED, with sales exceeding US$1 billion. Subsequently, the FDA approved both vardenafil [28] 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 [29] 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. [30] [31] 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. [24] 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, [32] 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. [33]

In October 2011, the US FDA approved tadalafil [34] 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.

Society and culture

Marketing

Cialis 5mg UK pack of 28 tablets Cialis 5mg UK.jpg
Cialis 5mg UK pack of 28 tablets

In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers. [35] Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the Grey Global Group, to run the Cialis advertising campaign. [36] 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." [36] 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?" [36] Cialis ads were unique among the ED drugs in mentioning specifics of the drug. [37] 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. [37] Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism. [37] Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson's halftime "wardrobe malfunction" overshadowed Cialis. [37] 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. [35] In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively. [37] 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. [38]

Economics

In Australia, tadalafil is subsidized through the Repatriation Pharmaceutical Benefits Scheme (RPBS) for patients with a specific accepted war- or service-related disability. [39]

In the US, a generic version of tadalafil is available. [40] 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. [41] [42]

In the UK, a generic version of tadalafil became available in November 2017, reducing its price per pill, and is available through the NHS.[ citation needed ] In China, CMOAPI is the largest manufacturer of Tadalafil powder. [43]

Research

Tadalafil is being studied for treating Peyronie's disease. [44] [45]

Related Research Articles

Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a penile erection with sufficient rigidity and duration for satisfactory sexual activity. It is the most common sexual problem in males and can cause psychological distress due to its impact on self-image and sexual relationships.

<span class="mw-page-title-main">Sildenafil</span> Drug for erectile dysfunction and hypertension

Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain symptoms in secondary Raynaud's phenomenon. It is unclear if it is effective for treating sexual dysfunction in females. It can be taken orally, intravenously, or through the sublingual route. Onset when taken orally is typically within twenty minutes and lasts for about two hours.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

Anorgasmia is a type of sexual dysfunction in which a person cannot achieve orgasm despite adequate sexual stimulation. Anorgasmia is far more common in females (4.6%) than in males and is especially rare in younger men. The problem is greater in women who are post-menopausal. In males, it is most closely associated with delayed ejaculation. Anorgasmia can often cause sexual frustration.

<span class="mw-page-title-main">Vardenafil</span> Chemical compound

Vardenafil, sold under the brand name Levitra among others, is a medication that is used for treating erectile dysfunction. It is a PDE5 inhibitor. It is taken by mouth.

Icos Corporation was an American biotechnology company and the largest biotechnology company in the U.S. state of Washington, before it was sold to Eli Lilly and Company in 2007. It was founded in 1989 by David Blech, Isaac Blech, Robert Nowinski, and George Rathmann, a pioneer in the industry and chief executive officer (CEO) and co-founder of Amgen. Icos focused on the development of drugs to treat inflammatory disorders. During its 17-year history, the company conducted clinical trials of twelve drugs, three of which reached the last phase of clinical trials. Icos also manufactured antibodies for other biotechnology companies.

<span class="mw-page-title-main">Isosorbide mononitrate</span> Chemical compound

Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in humans

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum of the clitoris and of the penis as well as the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Udenafil</span> Chemical compound

The drug udenafil is marketed under the trade name Zydena. It is within the PDE5 inhibitor class (which also includes avanafil, sildenafil, tadalafil, and vardenafil). Like other PDE5 inhibitors, it is used to treat erectile dysfunction. Udenafil was developed by Dong-A Pharmaceutical. It has fairly rapid onset of action (peak plasma concentration after 1 to 1.5 hours), and has long duration of action (plasma half-life of 11 to 13 hours). Udenafil's pharmacokinetics allows once-daily dosage (in addition to on-demand use). Typical doses are 100 and 200 mg. Udenafil is available in Korea, Russia, and the Philippines. It has not yet been approved for use in the United States by the U.S. Food and Drug Administration.

<span class="mw-page-title-main">Avanafil</span> Chemical compound

Avanafil is a PDE5 inhibitor approved for erectile dysfunction by the FDA on April 27, 2012 and by EMA on June 21, 2013. Avanafil is sold under the brand names Stendra and Spedra. It was invented at Mitsubishi Tanabe Pharma, formerly known as Tanabe Seiyaku Co., and licensed to Vivus Inc., which partnered with Menarini Group to commercialise Spedra in over forty European countries, Australia, and New Zealand. Metuchen Pharmaceuticals obtained exclusive rights within the United States.

<span class="mw-page-title-main">Herbal viagra</span> Class of herbal products said to treat erectile dysfunction

Herbal viagra is a herbal product advertised as treating erectile dysfunction. Many different products are advertised as herbal viagra, but with varying ingredients. No clinical trials or scientific studies support the effectiveness of any of these ingredients for the treatment of erectile dysfunction and some products have been found to contain drugs and other adulterants, and have been the subject of FDA and FTC warnings and actions to remove them from the market.

<span class="mw-page-title-main">Acetildenafil</span> Chemical compound

Acetildenafil (hongdenafil) is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil (Viagra) which has been detected in numerous different brands of "herbal aphrodisiac" products sold in convenience stores that claim to boost libido and alleviate erectile dysfunction.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

Alpha blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

<span class="mw-page-title-main">Lodenafil</span> Chemical compound

Lodenafil is a drug belonging to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. Like udenafil and avanafil it belongs to a new generation of PDE5 inhibitors.

<span class="mw-page-title-main">Mirodenafil</span> Chemical compound

Mirodenafil belongs to the drug class PDE5 inhibitors, which includes avanafil, sildenafil, tadalafil, udenafil, and vardenafil, and is the first-line treatment for erectile dysfunction. Developed by SK Chemicals Life Science, mirodenafil is marketed in Korea under the trade name Mvix, offered both as tablets and as orally dissolving films.

<span class="mw-page-title-main">Sulfoaildenafil</span> Chemical compound

Sulfoaildenafil (thioaildenafil) is a synthetic drug that is a structural analog of sildenafil (Viagra). It was first reported in 2005, and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

<span class="mw-page-title-main">Homosildenafil</span> Chemical compound

Homosildenafil is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil and vardenafil. Homosildenafil was first identified as an adulterant in sex enhancement products in 2003 and was more recently detected in dietary supplements.

Finasteride/tadalafil, sold under the brand name Entadfi, is a fixed-dose combination medication used for the treatment of benign prostatic hyperplasia (BPH). It contains finasteride and tadalafil. It is taken by mouth.

References

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  6. 1 2 3 "Adcirca- tadalafil tablet". DailyMed. 23 June 2022. Archived from the original on 6 March 2023. Retrieved 10 April 2023.
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