SILOFAST-4 D

Indications

• Benign prostatic hyperplasia

Dosage

Adults: 500 micrograms daily, with treatment review at 3–6 months and then every 6–12 months.

Mechanism of action

Dutasteride binds to both type I and type II isoenzymes of 5α-reductase, forming a stable complex that inhibits the conversion of testosterone to DHT. DHT is a key hormone in prostate development and growth, and by reducing its levels by more than 90%, dutasteride alleviates symptoms of BPH and improves urinary flow.

Pharmacodynamics

Dutasteride exhibits a dose-dependent reduction in circulating DHT levels, with maximum effects observed within 1-2 weeks after initial administration. Clinical studies have shown that median serum DHT concentrations were reduced by 85% and 90% after 1 and 2 weeks of daily dosing with 0.5 mg, respectively. Continuous administration of dutasteride maintains DHT levels suppressed in the majority of patients, and it may also lead to decreased serum prostate-specific antigen (PSA) levels in patients with prostate cancer.

Pharmacokinetics

Dutasteride is well absorbed after oral administration, with a peak plasma concentration typically reached within 1-2 hours. The drug has a long half-life, allowing for once-daily dosing. It is extensively metabolized in the liver, primarily by CYP3A4 and CYP3A5 enzymes, leading to the formation of several metabolites. The elimination half-life is approximately 5 weeks, which supports the need for regular follow-up and dose adjustment based on clinical response.

Contra-indications

• History of micturition syncope
• History of postural hypotension

Adverse effects

• Abdominal pain
• Anxiety
• Angioedema
• Arrhythmias
• Asthenia
• Chest pain
• Constipation
• Cough
• Depression
• Dizziness
• Diarrhoea
• Drowsiness
• Fatigue
• Gastrointestinal disturbances
• Hyperhidrosis
• Insomnia
• Myalgia
• Nasal congestion
• Nausea
• Oedema
• Palpitations
• Paraesthesia
• Postural hypotension
• Sexual dysfunction
• Skin reactions
• Syncope
• Vomiting
• Weight gain

Interactions

• Cobicistat increases exposure
• Idelalisib increases exposure
• Clarithromycin increases exposure
• Crizotinib unknown effect on exposure
• Imatinib unknown effect on exposure
• Letermovir unknown effect on exposure
• Nilotinib unknown effect on exposure
• Terazosin may increase risk of hypotension

Precautions

• Caution in elderly patients
• Caution in patients with history of prostate cancer
• Monitor for signs of hypotension and syncope
• Consider lower initial dose in patients with autonomic neuropathy

Pregnancy

Dutasteride is contraindicated in pregnancy due to potential harm to a male fetus.

Breast-feeding

Manufacturer advises avoiding use during breastfeeding due to potential for effects on the infant.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Dutasteride 0.5 mg capsules

Indications

• Benign prostatic hyperplasia
• Lower urinary tract symptoms associated with benign prostatic hyperplasia

Dosage

Adults: The usual recommended dose for adults is 8 mg once daily, taken with food.

Mechanism of action

Silodosin functions as an antagonist to alpha-1 adrenergic receptors, specifically exhibiting the highest selectivity for the alpha-1A subtype. By blocking these receptors, silodosin reduces smooth muscle tone in the prostate and bladder neck, alleviating bladder outlet obstruction and improving urinary symptoms. It is believed to relieve both voiding and storage symptoms associated with BPH by modulating smooth muscle contraction through G protein-coupled receptor signaling pathways.

Pharmacodynamics

Silodosin has a high affinity for alpha-1A adrenergic receptors, being 162-fold more selective than for the alpha-1B subtype and approximately 50-fold more than for the alpha-1D subtype. Clinical trials have demonstrated that silodosin enhances maximum urinary flow rate and improves both voiding and storage symptoms of BPH. Its onset of action occurs within two to six hours of oral administration. While it inhibits the human ether-a-go-go-related gene (HERG) tail current, its cardiovascular effects remain minimal. However, it may lead to intraoperative floppy iris syndrome (IFIS) in patients undergoing cataract surgery.

Pharmacokinetics

Silodosin is well absorbed after oral administration, with a rapid onset of action. It undergoes extensive hepatic metabolism, primarily via the cytochrome P450 system, resulting in various metabolites. The elimination half-life is approximately 13 hours, and it is predominantly excreted via the fecal route. Renal clearance is also significant, but dose adjustments may be necessary in patients with renal impairment due to altered pharmacokinetic profiles.

Contra-indications

• Severe hepatic impairment
• Concurrent use of strong CYP3A4 inhibitors

Adverse effects

• Ejaculation disorders
• Orthostatic hypotension
• Dizziness
• Nasal congestion
• Fatigue
• Diarrhea

Interactions

• Caution with other antihypertensive agents
• Caution with PDE5 inhibitors
• Strong CYP3A4 inhibitors may increase silodosin levels

Precautions

• Use with caution in patients with a history of orthostatic hypotension
• Consider risk of intraoperative floppy iris syndrome (IFIS) in cataract surgery
• Monitor for signs of hypotension

Pregnancy

Silodosin is not indicated for use in women and its safety during pregnancy has not been established.

Breast-feeding

Silodosin is not indicated for use in women and its safety during breastfeeding has not been established.

Storage

Store below 30°C in a dry place. Keep out of reach of children.

Formulations

• Capsules 4 mg
• Capsules 8 mg

Mechanism of action

The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT. Compared to a 70% reduction of serum DHT levels caused by [finasteride], a near-complete suppression of serum DHT-more than 90% is seen with dutasteride. By forming a stable complex with both type I and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under _in vitro_ and _in vivo_ conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor.

Pharmacodynamics

Dutasteride is a synthetic 4-azasteroid compound that selectively inhibits both the type I and type II isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT). Dutasteride works by reducing the levels of circulating DHT. It was also shown to reduce the size of the prostate gland, improve urinary flow, and symptoms of benign prostatic hyperplasia alone or in combination with tamsulosin. The effect of the reduction of DHT by dutasteride is dose-dependent, with the maximum effect observed within 1-2 weeks following initial administration. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. The serum concentrations of DHT were maintained to be decreased by more than 90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. As evident from the clinical studies, dutasteride may also cause decreases in serum PSA in the presence of prostate cancer.

Mechanism of action

The pathogenesis of benign prostatic hyperplasia is not fully understood: it is believed to involve several pathways, including inflammation, apoptosis, and cellular proliferation. Most drug therapies aim to alleviate symptoms of benign prostatic hyperplasia, silodosin included. Lower urinary tract symptoms of benign prostatic hyperplasia are categorized into three main groups: voiding or obstructive (hesitancy, slow stream, intermittency, incomplete emptying), storage or irritative (frequency, urgency, nocturia, urge urinary incontinence), and postmicturition (postvoid dribbling). Prostate contraction is the main contributor to lower urinary tract symptoms of benign prostatic hyperplasia. The smooth muscle tone of the prostate is regulated by α_1A-adrenoceptors, which are the most highly expressed subtype of α₁adrenoceptors in the human prostate tissue. It has been reported that blockade of α_1A-adrenoceptors relieves bladder outlet obstruction. Blockade of α_1D-adrenoceptors, another subtype found in prostate tissue, is believed to alleviate storage symptoms due to detrusor overactivity. α₁-adrenoceptors are G protein-coupled receptors: upon binding of its natural ligand, norepinephrine and epinephrine, leads to the activation of phospholipase C and downstream signalling molecules, including inositol triphosphate and diacylglycerol. Ultimately, there is an increase in intracellular calcium levels and, consequently, smooth muscle contraction. Silodosin is an antagonist of α₁-adrenoceptors, with the highest selectivity for the α_1A-adrenoceptor subtype. By blocking the α_1A-adrenoceptor signalling pathway, silodosin promotes prostatic and urethral smooth muscle relaxation, thereby improving lower urinary tract symptoms such as voiding. Silodosin also targets afferent nerves in the bladder, relieving bladder overactivity and storage symptoms.

Pharmacodynamics

Silodosin is an antagonist of α₁-adrenoceptors. It has the highest selectivity for the α_1A-adrenoceptor subtype, with a 162-fold greater affinity than α_1B-adrenoceptor and about a 50-fold greater affinity than for α_1D-adrenoceptor. In clinical trials, silodosin improved maximum urinary flow rate, voiding symptoms, and storage symptoms of benign prostatic hyperplasia. Following oral administration, silodosin had a rapid onset of effect in men, with early effects of relieving lower urinary tract symptoms occurring within two to six hours post-dose. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current; however, it has weak cardiovascular effects. As with all α₁-adrenoceptor antagonists blocking α₁-adrenoceptors in the iris dilator muscle, silodosin may cause intraoperative floppy iris syndrome (IFIS), which is characterized by small pupils and iris billowing during cataract surgery in patients taking α1-AR antagonists.