Silodosin (known by the trade names Silosoft in India, Urief in Japan, Rapaflo in North America, and Silodyx or Niksol in the European Union) is a medication for the symptomatic treatment of

benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...

(BPH). It acts as an α₁-adrenoceptor antagonist with high uroselectivity (selectivity for the

prostate The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...

Medical uses

Silodosin is used for the treatment of BPH in adult men.

Contraindications

According to European labels, silodosin has no contraindications apart from known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

. Another source names recurring

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...

, recurring urinary infections, uncontrolled macro

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...

bladder stone A bladder stone is a stone found in the urinary bladder. Signs and symptoms Bladder stones are small mineral deposits that can form in the bladder. In most cases bladder stones develop when the urine becomes very concentrated or when one is ...

hydronephrosis Hydronephrosis describes hydrostatic dilation of the renal pelvis and calyces as a result of obstruction to urine flow downstream. Alternatively, hydroureter describes the dilation of the ureter, and hydronephroureter describes the dilation of t ...

, combination with other α₁-antagonists or

dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...

s, and severe

renal The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

or hepatic impairment as contraindications. According to the FDA, silodosin is contraindicated with paxlovid, a drug used in treating COVID-19 ( https://www.fda.gov/media/155050/download ).

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. Other common adverse effects (in more than 1% of patients) are dizziness,

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

, diarrhoea, and clogged nose. Less common (0.1–1%) are

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

(fast heartbeat), dry mouth,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, skin reactions, and erectile dysfunction. Hypersensitivity reactions occur in fewer than 0.01% of patients. There have been reports about

intraoperative floppy iris syndrome Intraoperative floppy iris syndrome (IFIS) is a complication that may occur during cataract extraction in certain patients. This syndrome is characterized by a flaccid iris which billows in response to ordinary intraocular fluid currents, a propen ...

during

cataract extraction Cataract surgery, also called lens replacement surgery, is the removal of the natural lens of the eye (also called "crystalline lens") that has developed an opacification, which is referred to as a cataract, and its replacement with an intraoc ...

s. These side effects are similar to those of other α₁ antagonists.

Interactions

Combining silodosin with strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, significantly increases its concentrations in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

and its 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 UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltrans ...

alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NA ...

s, and

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...

s, 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 Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests tha ...

drugs or with

PDE5 inhibitor A phosphodiesterase type 5 inhibitor (PDE5 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 supplyi ...

s have been found in studies; although combination with other α₁-antagonists is not well studied.

Pharmacology

Mechanism of action

Silodosin has high affinity for the α_1A adrenergic receptor in the prostate, the

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...

, and the prostatic urethra. By this mechanism it relaxes the smooth muscle in these organs, easing urinary flow and other symptoms of BPH. on Rapaflo. Accessed 2020-01-03.

Pharmacokinetics

The absolute

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

after oral intake is 32%. Food has little effect on the AUC. When in the bloodstream, 96,6% of the substance are bound to blood

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s. Its main metabolite is silodosin

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

, which inhibits the α_1A receptor with 1/8 of the

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

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. Silodosin is almost completely excreted in the form of metabolites; 33.5% via the urine and 54.9% via the feces. The

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of silodosin is 11 hours on average, and that of the glucuronide is 18 hours or 24 hours. (Sources are contradictory on this.) File:Silodosin glucuronide.svg, Silodosin

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

History

Silodosin received its first marketing approval in Japan in May 2006, under the brand name ''Urief'', which is jointly marketed by

Kissei Pharmaceutical Kissei Pharmaceutical is a pharmaceutical company based in Matsumoto, Nagano, Japan. Products discovered or developed by Kissei include: * Difelikefalin * Fostamatinib (trade name Tavalisse) * Linzagolix * Mitiglinide (Glufast) * Remogliflozin e ...

and

Daiichi Sankyo is a global pharmaceutical company and the second-largest pharmaceutical company in Japan. It achieved JPY 981.8 billion in revenue in 2019. The company owns the American biotechnology company Plexxikon, American pharmaceutical company American R ...

. Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals (now

Allergan Allergan plc is an American, Irish-domiciled pharmaceutical company that acquires, develops, manufactures and markets brand name drugs and medical devices in the areas of medical aesthetics, eye care, central nervous system, and gastroenterology. ...

) in 2004.

AbbVie AbbVie is an American publicly traded biopharmaceutical company founded in 2013. It originated as a spin-off of Abbott Laboratories. History On October 19, 2011, Abbott Laboratories announced its plan to separate into two publicly traded compani ...

absorbed Allergan in 2019. The United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

and Health Canada approved silodosin under the brand name ''Rapaflo'' on 9 October 2008 and 11 January 2011, respectively.

Society and culture

Brand names

Other brand names include ''Urorec'' (European Union, Australia, Russia), ''Niksol'' (Croatia), ''Silorel'' (Jamaica), SiloSoft 'Sildoo'', ''Silodal'' ''Silofast'' (India), ''Thrupas'' (South Korea), and ''Flopadex'' (Egypt).

Research

As α_1A adrenoceptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm, a trial with 15 male volunteers was conducted. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 patients reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.

References

External links

* {{Portal bar , Medicine AbbVie brands Alpha-1 blockers Benzamides Indolines Organofluorides Phenethylamines Phenol ethers Primary alcohols Trifluoromethyl compounds