Silodosin

Silodosin is an antagonist of α1-adrenoceptors.

Silodosin is used in the treatment of Benign prostatic hyperplasia. It is also used in the treatment of Ureteral stones.

Silodosin is rapidly absorbed with a bioavailability of approx 32%. The volume of distribution is 49.5 L, with plasma protein binding of approx 97%. It is metabolized in the liver via glucuronidation (UGT2B7), alcohol and aldehyde dehydrogenase, and oxidative pathways, primarily CYP3A4 to the main metabolite, KMD-3213G (glucuronide conjugate), and gets excreted via feces (55%) and urine (34%). The elimination half-life of approx 13 hours (silodosin); approx 24 hours (KMD-3213G).

The onset of Action of Silodosin is within 2-6 hours.

The Duration of action of Silodosin is within 13.3 ± 8.07 hours.

The Tmax of Silodosin was Approx 3 hours.

The Cmax of Silodosin was found within 61.6 ± 27.54 ng/mL

The common side effects are dizziness, drowsiness, headache, weakness, Nausea, strong irregular heartbeat, swelling, and dizziness upon standing.

Silodosin is available in the form of a dosage form, such as capsules.

Silodosin is available in the USA, UK, Canada, Japan, India

Silodosin is a selective antagonist of post-synaptic α₁-adrenoreceptors in the prostate and bladder. Blockade of α₁-adrenoreceptors causes relaxation of smooth muscle resulting in improved urine flow and reduced BPH symptoms.

Silodosin is available in the form of a dosage form, such as capsules.

Silodosin capsules are taken orally with or without food.

Silodosin is used in the treatment of Benign prostatic hyperplasia. It is also used in the treatment of Ureteral stones.

Silodosin is an antagonist of α1-adrenoceptors. It has the highest selectivity for the α1A-adrenoceptor subtype, with a 162-fold greater affinity than α1B-adrenoceptor and about a 50-fold greater affinity than α1D-adrenoceptor. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current; however, it has weak cardiovascular effects

Silodosin is approved for its use in the following clinical indications:

● Benign prostatic hyperplasia:

Treatment of signs and symptoms of benign prostatic hyperplasia.

Although not approved, there has been certain label use documented for Silodosin, which include:

Ureteral stone(s)

Silodosin is available in various dosage strengths:4 mg, 8 mg.

Silodosin is available in the form of a dosage form, such as capsules.

Dose Adjustment in Kidney Patients:

● CrCl >50 mL/minute: No dosage adjustment necessary.

● CrCl 30-50 mL/minute: 4 mg once daily.

● CrCl <30 mL/minute: Use is contraindicated.

Dose Adjustment in Hepatic Impairment Patient

● Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

● Severe impairment (Child-Pugh class C): Use is contraindicated (has not been studied).

Dose Adjustment in Pediatric Patients.

Silodosin is not recommended for pediatric patients.

Silodosin is approved for the treatment of Benign prostatic hyperplasia.

Eat a low-fat diet: Eat a large variety of vegetables each day. Eat a few servings of fruit daily, and be sure to include citrus fruits. Participate in moderate to vigorous physical activity most days of the week.

Silodosin may be contraindicated in the following.

Hypersensitivity to silodosin or any component of the formulation, concurrent use with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir); severe renal impairment (CrCl <30 mL/minute); severe hepatic impairment (Child-Pugh class C)

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Concerns related to adverse effects:

• Floppy iris syndrome: Intraoperative floppy iris syndrome has been observed in cataract surgery patients who were on or were previously treated with alpha₁-blockers; causality has not been established, and there appears to be no benefit in discontinuing alpha-blocker therapy prior to surgery.

• Orthostatic hypotension/syncope: May cause significant orthostatic hypotension with or without syncope, especially with the first dose; anticipate a similar effect if therapy is interrupted for a few days, if the dosage is rapidly increased, or if another antihypertensive drug (particularly vasodilators) or a PDE-5 inhibitor (e.g., sildenafil, tadalafil, vardenafil) is introduced although coadministration of sildenafil or tadalafil with silodosin was not associated with a clinically significant risk of orthostatic hypotension in one clinical trial (MacDiarmid 2010). “First-dose” orthostatic hypotension may occur 4 to 8 hours after dosing; may be dose related. Patients should be cautioned about performing hazardous tasks, driving, or operating heavy machinery when starting new therapy or adjusting dosage upward.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment; contraindicated with severe impairment; not studied.

• Prostate cancer: It is recommended to rule out prostatic carcinoma before beginning therapy.

• Renal impairment: Use with caution in patients with moderate renal impairment; dosage adjustment recommended. Contraindicated in patients with severe impairment

Avoid taking alcohol with Silodosin as it may result in side effects like headache, dizziness, and faintness.

Teratogenic Effects

Pregnancy Category B.

Silodosin is not indicated for use in women.

An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13 to 25 times the maximum recommended human exposure or MRHE of silodosin via AUC). No statistically significant teratogenicity was observed at this dose.

Silodosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHD). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has a similar pharmacological activity to silodosin.

No effects on the physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day.

Salt Substitutes: Those who are taking Silodosin should avoid sodium, calcium, and magnesium-rich foods. The salts may reduce the blood-pressure-lowering effect of Silodosin.

The adverse reactions related to the molecule Silodosin can be categorized as

• Common Adverse effects: orthostatic hypotension, postural hypotension, syncope, floppy iris syndrome in cataract and glaucoma surgery, hypersensitivity reactions, and MI exacerbations.
• Less Common adverse effects: Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower, hoarseness, lightheadedness, fainting, rash, yellowing of the skin or eyes, fever, sore throat, chills, and other signs of infection.
• Rare Adverse effects: Pruritus, urticaria, skin desquamation including erythema multiforme, dermatitis exfoliative, and rarely, Stevens-Johnson syndrome.

The clinically relevant drug interactions of Silodosin are briefly summarized here.

Silodosin plasma concentration may be increased by moderate CYP3A4 inhibitors (e.g. diltiazem, erythromycin, verapamil), P-glycoprotein transport inhibitors (e.g. cyclosporin), and uridine diphosphate-glucuronosyltransferase (e.g. fluconazole, probenecid, valproic acid). Concomitant use with antihypertensive agents may increase the risk of adverse effects (orthostatic hypotension). Concomitant use of PDE-5 inhibitors (e.g., sildenafil) may lead to symptomatic hypotension.

Potentially Fatal: Significantly increased plasma concentration with strong CYP3A4 inhibitor (e.g. clarithromycin, itraconazole, ketoconazole, ritonavir). Additive cardiovascular effects with other α-adrenergic blockers.

Symptoms: Postural hypotension.

Management: Maintain the patient in the supine position. Induce vomiting or consider gastric lavage. Provide cardiovascular support if an overdose leads to hypotension.

Pharmacodynamics:

Silodosin is a selective antagonist of post-synaptic α1-adrenoreceptors in the prostate and bladder. Blockade of α1-adrenoreceptors causes relaxation of smooth muscle resulting in improved urine flow and reduced BPH symptoms. Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms.

Pharmacokinetics:

• Absorption:

It is rapidly absorbed. Bioavailability: Approx 32%. Time to peak plasma concentration: Approx 3 hours.

• Distribution:

The volume of distribution: 49.5 L. Plasma protein binding: Approx 97%.

• Metabolism:

Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD-3213G) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Coadministration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, fluconazole) may potentially increase exposure to silodosin. KMD-3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four times greater than that of silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin.

• Excretion:

Via feces (55%) and urine (34%). Elimination half-life: Approx 13 hours (silodosin); approx 24 hours (KMD-3213G).

1. https://www.mims.com/india/drug/info/Silodosin ?type=full&mtype=generic
2. https://www.uptodate.com/contents/Silodosin-drug-information?search=Silodosin-drug-in&usage_type=panel&kp_tab=drug_general&source=search_result&selectedTitle=1~37&display_rank=1#F162889
3. https://go.drugbank.com/drugs/DB00590
4. https://www.rxlist.com/consumer_Silodosin _cardura/drugs-condition.htm
5. https://reference.medscape.com/drug/cardura-xl-Silodosin -342343
6. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9880aad-5fbe-470b-a7a0-d963ba4bc98b.