Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Alpha1-adrenoceptor antagonist.
ATC code: G04C A02. Preparations for the exclusive treatment of prostatic disease.
Mechanism of action:
Tamsulosin binds selectively and competitively to postsynaptic alpha1-receptors, in particular to the subtype alpha1A, which bring about relaxation of the smooth muscle of the prostate, whereby tension is reduced.

Pharmacodynamic effects:
Tamsulosin increases the maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction.
It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha 1- blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

Paediatric Population
A double-blind, randomized, placebo-controlled, dose ranging study was performed in children with neuropathic bladder. A total of 161 children (with an age of 2 to 16 years) were randomized and treated at 1 of 3 dose levels of tamsulosin (low [0.001 to 0.002 mg/kg], medium [0.002 to 0.004 mg/kg], and high [0.004 to 0.008 mg/kg]), or placebo. The primary endpoint was number of patients who decreased their detrusor leak point pressure (LPP) to <40 cm H2O based upon two evaluations on the same day. Secondary endpoints were: Actual and percent change from baseline in detrusor leak point pressure, improvement or stabilization of hydronephrosis and hydroureter and change in urine volumes obtained by catheterisation and number of times wet at time of catheterisation as recorded in catheterisation diaries. No statistically significant difference was found between the placebo group and any of the 3 tamsulosin dose groups for either the primary or any secondary endpoints. No dose response was observed for any dose level.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Absorption
Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Absorption of tamsulosin is reduced by a recent meal. Uniformity of absorption can be promoted by the patient always taking tamsulosin after the same meal. Tamsulosin shows linear kinetics.

After a single dose of tamsulosin in the fed state, plasma levels of tamsulosin peak at around 6 hours and, in the steady state, which is reached by day 5 of multiple dosing, Cmax in patients is about two thirds higher than that reached after a single dose. Although this was seen in elderly patients, the same finding would also be expected in young ones.

There is a considerable inter-patient variation in plasma levels, both after single and multiple dosing.

Distribution
In man, tamsulosin is about 99% bound to plasma proteins and volume of distribution is small (about 0.2 l/kg).

Metabolism
Tamsulosin has a low first pass effect, being metabolised slowly. Most tamsulosin is present in plasma in the form of unchanged drug. It is metabolised in the liver.
In rats, hardly any induction of microsomal liver enzymes was seen to be caused by tamsulosin.
None of the metabolites are more active than the original compound.

Elimination
Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of the dose being present in the form of unchanged active substance.
After a single dose of tamsulosin in the fed state, and in the steady state in patients, elimination half-lives of about 10 and 13 hours respectively have been measured.