Indications
Silodosin is specifically indicated for the management of signs and symptoms associated with benign prostatic hyperplasia (BPH). It is important to note that silodosin is not prescribed for the treatment of hypertension.
Pharmacodynamics
As an α1-adrenoceptor antagonist, silodosin exhibits a high selectivity particularly towards the α1A-adrenoceptor subtype, demonstrating a 162-fold increased affinity compared to the α1B-adrenoceptor, and a 50-fold higher affinity relative to the α1D-adrenoceptor. Clinical trials have highlighted silodosin's effectiveness in enhancing maximum urinary flow rates and addressing both voiding and storage symptoms related to BPH. Upon oral administration, silodosin acts swiftly, offering symptom relief from lower urinary tract issues within two to six hours. While it inhibits the human ether-a-go-go-related gene (HERG) tail current, its cardiovascular impacts are minimal. Patients on silodosin may experience intraoperative floppy iris syndrome (IFIS), notably during cataract surgery, attributable to the blockage of α1-adrenoceptors in the iris dilator muscle.
Absorption
Silodosin has an absolute bioavailability of roughly 32%. When administered orally at a dose of 8 mg per day to healthy male individuals, it achieves a maximum concentration (Cmax) of 61.6 ± 27.54 ng/mL and an area under the curve (AUC) of 373.4 ± 164.94 ng x hr/mL, with a time to maximum concentration (Tmax) of 2.6 ± 0.90 hours. The primary metabolite, silodosin glucuronide or KMD-3213G, presents an AUC that is three to four times higher than silodosin itself. A meal with moderate fat or calorie content can reduce Cmax by 18% to 43% and AUC by 4% to 49%, delaying Tmax by approximately one hour. Despite these effects, it is recommended to take the drug with meals to prevent potential adverse reactions linked to elevated plasma drug levels.
Metabolism
Silodosin is primarily metabolized into silodosin glucuronide (KMD-3213G) via glucuronidation, facilitated by UDP-glucuronosyltransferase 2B7 (UGT2B7). This active metabolite reaches plasma concentrations (AUC) roughly four times greater than the parent compound. The secondary metabolite, KMD-3293, arises from dehydrogenation, driven by alcohol and aldehyde dehydrogenases, but exhibits negligible pharmacological activity. Silodosin also undergoes oxidative metabolism primarily through CYP3A4. Beyond glucuronidation, dehydrogenation, and oxidation, silodosin experiences pathways such as dealkylation (KMD-3289), N-dealkylation, hydroxylation, glucosylation, and sulfate conjugation, with its metabolites potentially engaging in further metabolic transformations.
Mechanism of Action
The pathogenesis of benign prostatic hyperplasia (BPH) remains incompletely elucidated, but it is believed to involve multiple pathways, including inflammation, apoptosis, and cellular proliferation. Pharmacological treatments for BPH, such as silodosin, primarily aim to alleviate its associated symptoms. These lower urinary tract symptoms are classified into three categories: voiding or obstructive symptoms (such as hesitancy, slow stream, intermittency, and incomplete bladder emptying), storage or irritative symptoms (including frequency, urgency, nocturia, and urge urinary incontinence), and postmicturition symptoms (characterized by postvoid dribbling). A major factor contributing to these symptoms is the contraction of the prostate, which is regulated by α1A-adrenoceptors, the most abundant subtype of α1-adrenoceptors in human prostate tissue. Blocking α1A-adrenoceptors has been shown to relieve bladder outlet obstruction, while inhibiting α1D-adrenoceptors, another subtype found in prostate tissue, is thought to alleviate storage symptoms associated with detrusor overactivity. α1-adrenoceptors are G protein-coupled receptors that, upon activation by their natural ligands (norepinephrine and epinephrine), initiate a signaling cascade involving phospholipase C and downstream molecules such as inositol triphosphate and diacylglycerol. This results in increased intracellular calcium levels and subsequent smooth muscle contraction. Silodosin acts as an antagonist of α1-adrenoceptors, with high selectivity for the α1A-adrenoceptor subtype. By inhibiting the α1A-adrenoceptor signaling pathway, silodosin facilitates the relaxation of prostatic and urethral smooth muscle, thereby ameliorating symptoms related to voiding. Additionally, silodosin impacts afferent nerves in the bladder, reducing bladder overactivity and storage symptoms.
