Duactam Mechanism of Action

Pharmacology: Pharmacodynamics: Tadalafil: Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion, which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Tamsulosin: 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.
Tamsulosin increases 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. Alpha1-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with Tamsulosin.
Pharmacokinetics: Tadalafil: Absorption: Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of Tadalafil following oral dosing has not been determined.
The rate and extent of absorption of Tadalafil are not influenced by food, thus Tadalafil may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution: The mean volume of distribution is approximately 63 liters, indicating that Tadalafil is distributed into tissues. At therapeutic concentrations, 94% of Tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolized by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than Tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for Tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Tamsulosin: Absorption: Tamsulosin hydrochloride administered as prolonged release tablets is absorbed from the intestine. Under fasting conditions, approximately 57% of the administered dose is estimated to be absorbed. A consistent slow release of tamsulosin is maintained over the whole pH range encountered in the gastro-intestinal tract with little fluctuation over 24 hours. The extent of absorption is increased by 64% and 149% (AUC and Cmax respectively) by a high fat meal compared to fasted. After a single dose of Tamsulosin in the fasted state, plasma levels of tamsulosin peak at a median time of 6 hours. In steady state, which is reached by day 4 of multiple dosing, plasma levels of tamsulosin peak at 4 to 6 hours in the fasted and fed state. Peak plasma levels 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 Tamsulosin, 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 after 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 metabolized slowly.
Most tamsulosin is present in plasma in the form of unchanged drug. 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 hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride.
No dose adjustment is warranted in hepatic insufficiency.
None of the metabolites are more active than the original compound.
Elimination: Tamsulosin and its metabolites are mainly excreted in the urine. The amount excreted as unchanged drug is estimated to be about 4-6% of the dose, administered as Tamsulosin.
After a single dose of Tamsulosin, and in steady state, elimination half-lives of about 19 and 15 hours, respectively, have been measured.
No dose adjustment is necessary in patients with renal impairment.
Toxicology: Preclinical Safety Data: Tadalafil: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity or fetotoxicity in rats or mice that received up to 1000 mg/kg/day Tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day.
In the pregnant rat, the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg dose.
There was no impairment of fertility in male and female rats. In dogs given Tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs.
Tamsulosin: 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.