silodosin

{{Infobox drug

| Verifiedfields = changed

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| verifiedrevid = 464390579

| image = Silodosin Structural Formula V.1.svg

| width =

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| caption =

| pronounce =

| tradename = Urief, Rapaflo, Silodyx, others

| Drugs.com = {{Drugs.com|monograph|silodosin}}

| MedlinePlus = a609002

| pregnancy_AU =

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = By mouth

| class = α₁ blocker

| ATC_prefix = G04

| ATC_suffix = CA04

| ATC_supplemental =

| legal_AU = S4

| legal_AU_comment = {{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | access-date=9 April 2023}}{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}

| legal_BR =

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment =

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| legal_UK =

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| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Rapaflo- silodosin capsule | website=DailyMed | date=1 December 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da0314f6-b1d6-44ee-8b1e-f763dbb8613f | access-date=5 March 2023}}

| legal_EU = Rx-only

| legal_EU_comment = {{cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/silodyx|title=Silodyx EPAR |publisher=European Medicines Agency (EMA) |date=2010-01-10}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

| legal_UN =

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| legal_status = Rx-only

| bioavailability = 32%

| protein_bound = 96.6%

| metabolism = Liver glucuronidation (UGT2B7-mediated); also minor CYP3A4 involvement

| metabolites =

| onset =

| elimination_half-life = 13±8 hours{{citation needed|date=January 2020}}

| duration_of_action =

| excretion = 33.5% Kidney, 54.9% fecal

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 160970-54-7

| CAS_supplemental =

| PubChem = 5312125

| IUPHAR_ligand = 493

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB06207

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4471557

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = CUZ39LUY82

| KEGG = D01965

| ChEBI =

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 24778

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| PDB_ligand =

| synonyms = KAD-3213, KMD-3213

| IUPAC_name = 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide

| C = 25

| H = 32

| F = 3

| N = 3

| O = 4

| SMILES = FC(F)(F)COc3ccccc3OCCN[C@H](C)Cc1cc2c(c(c1)C(=O)N)N(CC2)CCCO

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C25H32F3N3O4/c1-17(30-8-12-34-21-5-2-3-6-22(21)35-16-25(26,27)28)13-18-14-19-7-10-31(9-4-11-32)23(19)20(15-18)24(29)33/h2-3,5-6,14-15,17,30,32H,4,7-13,16H2,1H3,(H2,29,33)/t17-/m1/s1

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = PNCPYILNMDWPEY-QGZVFWFLSA-N

| density =

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}}

Silodosin, sold under the brand name Urief among others, is a medication used for the symptomatic treatment of benign prostatic hyperplasia. It acts as an alpha-1 adrenergic receptor antagonist.

The most common side effect is a reduction in the amount of semen released during ejaculation.

Medical uses

Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia.{{cite web|url=https://www.ema.europa.eu/documents/product-information/urorec-epar-product-information_en.pdf|title=Urorec: EPAR – Product Information|publisher=European Medicines Agency|date=2019-11-21}}

Contraindications

Silodosin is contraindicated for people with kidney impairment or severe liver impairment.

According to European labels, silodosin has no contraindications apart from known hypersensitivity.{{cite book|title=Austria-Codex|editor=Haberfeld, H|at=Urorec 4 mg-Hartkapseln|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2019|language=de}} Another source names recurring urinary retention, recurring urinary infections, uncontrolled macrohematuria, bladder stones, hydronephrosis, combination with other α₁-antagonists or dopamine agonists, and severe renal or hepatic impairment as contraindications.{{cite book|title=Arzneistoff-Profile|year=1982 |editor=Dinnendahl, V |editor2=Fricke, U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|isbn=978-3-7741-9846-3|language=de}} According to the US Food and Drug Administration (FDA), silodosin is contraindicated with paxlovid, a drug used in treating COVID-19.{{Cite report |url=https://www.fda.gov/media/155050/download |title=Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid |date=February 2023 |publisher=Pfizer |page=7}}

Side effects

The most common adverse effect is loss of seminal emission. This seems to be caused by silodosin's high selectivity for α_1A receptors.

Intraoperative floppy iris syndrome occurs in some people taking alpha adrenoreceptor antagonists and may lead to complications during cataract surgery.

Other common adverse effects (in more than 1% of patients) are dizziness, orthostatic hypotension, diarrhea, and clogged nose. Less common (0.1–1%) are tachycardia (fast heartbeat), dry mouth, nausea, skin reactions, and erectile dysfunction. Hypersensitivity reactions occur in fewer than 0.01% of patients. There have been reports about intraoperative floppy iris syndrome during cataract extractions.

Interactions

Combining silodosin with strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, significantly increases its concentrations in the blood plasma and its area under the curve (area under the curve (AUC)). Less potent CYP3A4 inhibitors such as diltiazem have a less pronounced effect on this parameters, which is not considered clinically significant. Inhibitors and inducers of the enzyme UGT2B7, alcohol dehydrogenases, and aldehyde dehydrogenases, as well as the transporter P-glycoprotein (P-gp), may also influence silodosin concentrations in the body. Digoxin, which is transported by P-gp, is not affected by silodosin; this means that silodosin does not significantly inhibit or induce P-gp.

No relevant interactions with antihypertensive drugs or with PDE5 inhibitors have been found in studies; although combination with other α₁-antagonists is not well studied.

Pharmacology

= Mechanism of action =

Silodosin is an alpha adrenoreceptor antagonist. It works by blocking receptors called alpha-1A adrenoreceptors in the prostate gland, the bladder and the urethra (the tube that leads from the bladder to the outside of the body). When these receptors are activated, they cause the muscles controlling the flow of urine to contract. By blocking these receptors, silodosin allows these muscles to relax, making it easier to pass urine and relieving the symptoms of BPH.

Silodosin has high affinity for the alpha_1A-adrenergic receptor in the prostate, the bladder, and the prostatic urethra. By this mechanism, it relaxes the smooth muscles in these organs, easing urinary flow and other symptoms of benign prostatic hyperplasia.

= Pharmacokinetics =

The absolute bioavailability after oral intake is 32%. Food has little effect on the area under the curve. When in the bloodstream, 96,6% of the substance are bound to blood plasma proteins. Its main metabolite is silodosin glucuronide, which inhibits the α_1A receptor with 1/8 of the affinity of the parent substance. 91% of the glucuronide are bound to plasma proteins. The enzyme mainly responsible for the formation of the glucuronide is UGT2B7. Other enzymes involved in the metabolism are alcohol dehydrogenases, aldehyde dehydrogenases and CYP3A4.

File:Silodosin glucuronide.svg|Silodosin glucuronide

File:Silodosin acid.svg|KMD-3293, the other main metabolite

History

Silodosin received its first marketing approval in Japan in May 2006,{{cite press release | title=Kissei Acquired Marketing Approval for Urief Capsule, a Novel Drug for Dysuria associated with Benign Prostatic Hyperplasia | website=Kissei Pharmaceutical Co., Ltd. | date=23 January 2006 | url=https://www.kissei.co.jp/e_contents/news/2006/20060123-700.html | access-date=5 March 2023}} under the brand name Urief, which is jointly marketed by Kissei Pharmaceutical and Daiichi Sankyo.

Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals (now Allergan) in 2004.{{cite web | title=Watson Pharmaceuticals, Inc. Announces Agreement With Kissei Pharmaceutical Co., Ltd. For Novel Urology Drug Candidate | website=BioSpace | date=22 April 2004 | url=https://www.biospace.com/article/watson-pharmaceuticals-inc-announces-agreement-with-kissei-pharmaceutical-co-ltd-for-novel-urology-drug-candidate-/ | access-date=5 March 2023 | archive-date=6 March 2023 | archive-url=https://web.archive.org/web/20230306053349/https://www.biospace.com/article/watson-pharmaceuticals-inc-announces-agreement-with-kissei-pharmaceutical-co-ltd-for-novel-urology-drug-candidate-/ | url-status=dead }} AbbVie absorbed Allergan in 2019. The FDA and Health Canada approved silodosin under the brand name Rapaflo in October 2008,{{cite web | title=Drug Approval Package: Rapaflo (Silodosin) NDA #022206 | website=U.S. Food and Drug Administration (FDA) | date=14 November 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022206s000TOC.cfm | access-date=5 March 2023}}{{cite web |url=https://www.drugs.com/nda/silodosin_080212.html |title=Drugs.com, Watson Announces Silodosin NDA Accepted for Filing by FDA for the Treatment of Benign Prostatic Hyperplasia |access-date=2008-02-13 }} and January 2011,{{cite web |title=Summary Basis of Decision - Rapaflo |url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailOne.php?lang=en&linkID=SBD00120 |website=Health Canada |access-date=8 January 2021 |date=4 May 2011}} respectively.

Society and culture

= Brand names =

Other brand names include Urorec,{{cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/urorec|title=Urorec EPAR |publisher=European Medicines Agency|date=2019-11-21}} Niksol, Silorel, Rapilif, Silotrif, Sildoo, Silodal Silofast, Alphacept, Thrupas, and Flopadex.{{citation needed|date=January 2020}}

Research

Alpha-1 adrenergic receptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 participants reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.{{cite journal |vauthors=Kobayashi K, Masumori N, Kato R, Hisasue S, Furuya R, Tsukamoto T |title=Orgasm is preserved regardless of ejaculatory dysfunction with selective alpha1A-blocker administration |journal=Int J Impot Res |volume=21 |issue=5 |pages=306–10 |date=December 2009 |pmid=19536124 |pmc=2834370 | doi = 10.1038/ijir.2009.27 | doi-access = free | title-link = doi }}