Concore AM Mechanism of Action

Pharmacology: Pharmacodynamics: Bisoprolol: Bisoprolol is a β₁-selective adrenoceptor-blocking agent lacking intrinsic stimulating and relevant membrane stabilizing activity.
It only shows very low affinity to the β₂-receptor of the smooth muscles of bronchi and vessels as well as to the β₂-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and β₂-mediated metabolic effects. Its β₁-selectivity extends beyond the therapeutic dose range. Bisoprolol has no pronounced negative inotropic effect.
Bisoprolol reaches its maximal effect 3-4 hours after oral administration.
The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage. The maximal antihypertensive effect of bisoprolol treatment is generally reached after 2 weeks.
In acute administration in patients with coronary heart disease without chronic heart failure, bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration, the initially elevated peripheral resistance decreases. Among others, the depression of plasma renin activity is discussed as a mechanism of action underlying the antihypertensive effect of beta-blockers.
Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle (slow channel blocker or calcium ion antagonist).
The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle causing reduction in peripheral vascular resistance.
The precise mechanism by which it relieves angina has not been fully determined, it may have the following two actions: It dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload). Since it does not cause reflex tachycardia, myocardial energy consumption and oxygen requirement will be reduced.
By means of dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions, it improves oxygen supply. By the previously mentioned mechanism, it increases myocardial oxygen delivery even in case of coronary artery spasm (Prinzmetal's or variant angina).
Bisoprolol and Amlodipine Combination: This combination allows to increase the antihypertensive and anti-anginal efficacy by complementary mechanism of actions of the two active compounds: vasoselective effect of the calcium channel blocker amlodipine (decrease of peripheral resistance) and cardioselective beta-blocker bisoprolol (decrease of cardiac output).
Pharmacokinetics: Bisoprolol: The kinetics of bisoprolol are linear and independent of age.
Absorption: Bisoprolol is absorbed almost completely (>90%) from the gastrointestinal tract. Due to the small first pass effect (approximately 10%), its absolute bioavailability is approximately 90% after oral administration.
Distribution: Its distribution volume is 3.5 L/Kg. The plasma protein binding of bisoprolol is about 30%.
Metabolism and Elimination: Bisoprolol is excreted from the body by two routes. 50% is metabolized by the liver to inactive metabolites, which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolized form. Total clearance is approximately 15 L/h.
The elimination half-life in plasma is 10-12 hours.
Patients with impaired function of the liver or kidneys: Since the elimination takes place in the kidneys and the liver to the same extent, a dosage adjustment is not required for patients with mild to moderate impairment of the liver or the kidneys.
Amlodipine: Absorption: After oral administration, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Its bioavailability is unaffected by food ingestion. Absolute bioavailability has been estimated to be between 64 and 80%.
Distribution: The volume of distribution is 21 L/Kg. Steady state plasma concentration (5-15 ng/mL) is reached after 7-8 days of consecutive daily dosing. In vitro studies have shown that 93-98% of circulating amlodipine is bound to plasma proteins.
Metabolism and Elimination: Amlodipine is extensively metabolized (approximately 90%) by the liver to inactive pyridine derivatives. 10% of the parent compound and 60% of inactive metabolites excreted in the urine, 20-25% with feces.
Decrease of plasma concentration shows biphasic characteristics. The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing.
Total clearance is 7 mL/min/Kg (in case of 60 Kg-patient: 25 L/h). In elderly patients, this value is 19 L/h.
Use in elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group study.
Patients with impaired renal function: Amlodipine is extensively metabolized into inactive metabolites. 10% of the parent compound is excreted unchanged in the urine. The changes in the plasma concentration of amlodipine are not related to the degree of renal impairment. These patients can be treated with a normal dosage of amlodipine. Amlodipine is not dialyzable.
Patients with impaired hepatic function: The half-life of amlodipine is prolonged in patients with impaired hepatic function.
Interaction studies: Pharmacokinetic interaction studies: With concomitant use of amlodipine with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively, the plasma concentration of amlodipine increased by 22% and 50% respectively. There is no data available regarding the effect of CYP3A4 inducers on amlodipine.
Bisoprolol and Amlodipine Combination: A pharmacokinetic interaction study demonstrated no interaction between the two compounds.