DUTASOLIN

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 (BPH)
• Urinary flow obstruction due to prostatic enlargement

Dosage

Adults: The usual starting dose is 400 micrograms once daily, taken approximately 30 minutes after the same meal each day. If necessary, the dose may be increased to a maximum of 800 micrograms once daily.

Mechanism of action

Tamsulosin selectively blocks alpha-1A and alpha-1D adrenergic receptors, which are predominantly found in the prostate and bladder. By inhibiting these receptors, tamsulosin promotes relaxation of the smooth muscle in the prostate and bladder, leading to improved urinary flow and reduced urinary retention symptoms. Its selectivity minimizes cardiovascular side effects typically associated with non-selective alpha blockers.

Pharmacodynamics

Tamsulosin exhibits high affinity for alpha-1A adrenoceptors, being 3.9-38 times more selective for these receptors compared to alpha-1B, which are more prevalent in vascular tissues. This selectivity enhances its therapeutic effectiveness in managing urinary symptoms while reducing risks of adverse effects such as orthostatic hypotension. The pharmacodynamic profile indicates a potential for improved patient tolerance and safety compared to less selective alpha blockers.

Pharmacokinetics

Tamsulosin is well-absorbed following oral administration, with peak plasma concentrations typically reached within 4 to 6 hours. The drug has a bioavailability of approximately 57%, and its metabolism primarily occurs in the liver via cytochrome P450 enzymes (CYP2D6 and CYP3A4). The elimination half-life is roughly 9 to 15 hours, allowing for once-daily dosing. Tamsulosin is primarily excreted in the urine as metabolites, with minimal unchanged drug in the urine.

Contra-indications

• Hypersensitivity to tamsulosin or any of its components
• Severe hepatic impairment

Adverse effects

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

Interactions

• Other antihypertensive agents may potentiate the hypotensive effect
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase tamsulosin levels
• CYP2D6 inhibitors may alter tamsulosin metabolism

Precautions

• Use with caution in patients with a history of orthostatic hypotension
• Caution in patients with renal impairment
• Monitor for signs of intraoperative floppy iris syndrome during cataract surgery

Pregnancy

Tamsulosin is not indicated for use in pregnancy. Its effects on fetal development are not well studied.

Breast-feeding

It is not known whether tamsulosin is excreted in human breast milk. Caution should be exercised when administered to nursing women.

Storage

Store below 30°C. Keep in the original package to protect from moisture.

Formulations

• Capsules (0.4 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

Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. Tamsulosin hydrochloride is a sulfamoylphenethylamine-derivative alpha1-adrenergic blocking agent. The drug is pharmacologically related to doxazosin, prazosin, and terazosin; however, unlike these drugs, tamsulosin has higher affinity and selectivity for alpha1A-adrenergic receptors, which are mainly located in nonvascular smooth muscle (eg, prostate), than for alpha1B-adrenergic receptors located in vascular smooth muscle (eg, internal iliac artery). Results of in vitro studies indicate that tamsulosin has 7-38 times greater affinity for alpha1A-adrenoceptors than for alpha1B-adrenoceptors; the drug has about 12 times greater affinity for alpha1-adrenergic receptors in the prostate than for those in the aorta. Such selectivity of tamsulosin for alpha1A-receptors may result in a reduced incidence of adverse cardiovascular effects (eg, syncope, dizziness, hypotension). On a molar basis, the alpha1-adrenergic receptor affinity of tamsulosin is about 6 times that of prazosin when tested in human prostatic tissue. Because of the prevalence of alpha-receptors on the prostate capsule, prostate adenoma, and bladder trigone and the relative absence of these receptors on the bladder body, alpha-adrenergic blocking agents decrease urinary outflow resistance in men. The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resist

Pharmacodynamics

Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension.