Tamsulosin Other names: Tamsulosin hydrochloride

Tamsulosin binds selectively and competitively to the postsynaptic α₁-adrenoceptors, in particular to subtypes α_1A and α_1D. It brings about relaxation of prostatic and urethral smooth muscle, 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.

These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterisation is significantly delayed.

α₁-adrenoceptor antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

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 breakfast or the first meal of the day. 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, C_max 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).

Biotransformation

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.

In vitro results suggest that CYP3A4 and also CYP2D6 are involved in metabolism, with possible minor contributions to tamsulosin hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride.

None of the metabolites are more active than the original compound.

No dose adjustment is warranted in patients with mild to moderate hepatic insufficiency.

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of unchanged drug. 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.

No dose adjustment is necessary in patients with renal impairment.

Single and repeat dose toxicity studies were performed in mice, rats and dogs. In addition reproduction toxicity studies were performed in rats, carcinogenicity in mice and rats and in vivo and in vitro genotoxicity were examined. The general toxicity profile as seen with high doses of tamsulosin is consistent with the known pharmacological actions of the alpha-adrenergic blocking agents. At very high dose levels the ECG was altered in dogs. This response is considered to be not clinically relevant. Tamsulosin showed no relevant genotoxic properties.

Increased incidences of proliferative changes of mammary glands of female rats and mice have been reported. These findings which are probably mediated by hyperprolactinaemia and only occurred at high dose levels are regarded as irrelevant.