CLINICAL PHARMACOLOGY
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. Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 -adrenoceptor subtypes have been identified: alpha1A , alpha1B and alpha 1D ; their distribution differs between human organs and tissue. Approximately 70% of the alpha1- receptors in human prostate are of the alpha1A subtype.
FLOMAX capsules are not intended for use as an antihypertensive drug. Pharmacokinetics The pharmacokinetics of tamsulosin HCl have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg.
Metabolism: There is no enantiometric bioconversion from tamsulosin HCl [R(-) isomer] to the S( + ) isomer in humans. Tamsulosin HCl is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. Additionally, the cytochrome P450 enzymes that primarily catalyze the Phase I metabolism of tamsulosin HCl have not been conclusively identified. Therefore, possible interactions with other cytochrome P450 metabolized compounds cannot be discerned with current information. The metabolites of tamsulosin HCl undergo extensive conjugation to
glucuronide or sulfate prior to renal excretion. Incubations with human liver microsomes showed no evidence of clinically significant metabolic
interactions between tamsulosin HCl and amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of the in vitro testing of the tamsulosin HCl interaction with diclofenac and warfarin were equivocal.
Excretion: On administration of the radiolabeled dose of tamsulosin HCl to four healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin HCl in plasma range from five to seven hours. Because of absorption rate-controlled pharmacokinetics with FLOMAX capsules, the apparent half-life of tamsulosin HCl is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population. Tamsulosin HCl undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h). Special Populations: Geriatrics (Age): Cross-study comparison of FLOMAX capsules overall exposure
(AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin HCl may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin HCl binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years.
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