Harnal OCAS Mechanism of Action

Pharmacotherapeutic group: α₁-adrenoceptor antagonists.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Pharmacodynamic effects: Harnal OCAS 400 mcg Film-coated Tablet increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in prostate and urethra thereby improving voiding symptoms.
It also improves the storage symptoms in which bladder instability plays an important role.
These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterization 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 Harnal OCAS 400 mcg Film-coated Tablet.
Pharmacokinetics: Absorption: Harnal OCAS 400 mcg Film-coated Tablet is a prolonged release tablet of the non-ionic gel matrix type. The OCAS (Oral Controlled Absorption System) formulation provides consistent slow release of tamsulosin, resulting in an adequate exposure, with little fluctuation, over 24 hours.
Tamsulosin administered as Harnal OCAS 400 mcg Film-coated Tablet is absorbed from the intestine. Under fasting conditions, of the administered dose, approximately 57% is estimated to be absorbed.
The rate and extent of absorption of tamsulosin administered as Harnal OCAS 400 mcg Film-coated Tablet are not affected by a low-fat meal. The extent of absorption is increased by 64% and 149% (AUC and C_max respectively) by a high-fat meal compared to fasted.
Tamsulosin shows linear pharmacokinetics.
After single dose of Harnal OCAS 400 mcg Film-coated Tablet in the fasted state, plasma concentrations of tamsulosin peak at a median time of 6 hours. In steady state, which is reached by day 4 of multiple dosing, plasma concentrations of tamsulosin peak at 4 to 6 hours, in the fasted and fed state. Peak plasma concentrations increase from approximately 6 ng/mL after the first dose to 11 ng/mL in steady state.
As a result of the prolonged release characteristics of Harnal OCAS 400 mcg Film-coated Tablet the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasted and fed conditions.
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. The volume of distribution is small (about 0.2 L/kg).
Metabolism: Tamsulosin has a low first pass effect, being metabolized slowly. Most tamsulosin is present in plasma in the form of unchanged active substance. It is metabolized 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 metabolism by other CYP isozymes. Inhibition of hepatic drug metabolizing enzymes may lead to increased exposure to tamsulosin (see PRECAUTIONS and INTERACTIONS).
None of the metabolites is more active than the original compound.
Excretion: Tamsulosin and its metabolites are mainly excreted in the urine. The amount excreted as unchanged active substance is estimated to be about 4-6% of the dose, administered as Harnal OCAS 400 mcg Film-coated Tablet.
After single dose of Harnal OCAS 400 mcg Film-coated Tablet and in steady state, elimination half-lives of about 19 and 15 hours, respectively, have been measured.
Toxicology: Pre-Clinical Safety Data: Single and repeat dose toxicity studies were performed in mice, rats and dogs. In addition, reproduction toxicity 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 α₁-adrenoceptor antagonists.
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 hyperprolactinemia and only occurred at high dose levels, are regarded as irrelevant.