onditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.
Tamsulosin: 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.
Tamsulosin, an alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least 3discrete alpha1-adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptors in human prostate are of the alpha1A subtype. Tamsulosin is not intended for use as an antihypertensive.
12.2 Pharmacodynamics
Dutasteride:Effect on 5 Alpha-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1 to 2weeks. After 1and 2weeks of daily dosing with dutasteride 0.5mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5mg/day for 4years, the median decrease in serum DHT was 94% at 1year, 93% at 2years, and 95% at both 3 and 4years. The median increase in serum testosterone was 19% at both 1 and 2years, 26% at 3years, and 22% at 4years, but the mean and median levels remained within the physiologic range.
In patients with BPH treated with 5mg/day of dutasteride or placebo for up to 12weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93pg/g, respectively, P<0.001).
Adult males with genetically inherited type2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase deficiency have been observed in these individuals.
Effects on Other Hormones: In healthy volunteers, 52weeks of treatment with dutasteride 0.5mg/day (n=26) resulted in no clinically significant change compared with placebo (n=23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8weeks (97.1ng/dL, P<0.003) and thyroid-stimulating hormone at 52weeks (0.4mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8weeks and 12.4% for thyroid-stimulating hormone at 52weeks. After stopping dutasteride for 24weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In patients with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled study, there was |
