Concor AMLO Mechanism of Action

Pharmacotherapeutic group: Beta blocking agents, selective, and other antihypertensives. ATC code: C07 FB 07.
Pharmacology: Pharmacodynamics: Mechanism of action of 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 dilation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions it improves oxygen supply. By the previously mentioned mechanism it increases myocardial oxygen delivery even in cases of coronary artery spasm (Prinzmetal's or variant angina).
Pharmacodynamic effects: In patients with hypertension, once daily dosing of provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hour interval. Due to the slow onset of action, acute hypotension is not a feature of its administration.
In patients with angina, by once daily administration it increases total exercise time, time to angina onset, and time to significant ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablets consumption.
It has not been associated with any adverse metabolic effects: it had no effect on the level of plasma lipids, blood sugar and serum uric acid and it was suitable for use in patients with asthma.
Mechanism of action of bisoprolol: Bisoprolol is a potent, highly β₁-selective adrenoreceptor-blocking agent devoid of intrinsic sympathomimetic activity (ISA) and without relevant membrane stabilising activity. It only shows low affinity to the β₂-receptor of the smooth muscles of bronchi and vessels as wells 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 explicit negative inotropic effect. Bisoprolol has 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.
It usually exerts its maximal antihypertensive effect 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.
Antihypertensive effect of beta-blockers is among others due to decrease of renin activity.
Pharmacodynamic effects of the combination product: 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: 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 metabolised (approx. 90%) by the liver to inactive pyridine derivates. 10% of the parent compound and 60% of inactive metabolites excreted in the urine, 20-25% with faeces. 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 7ml/min/kg (in case of 60 kg-patient: 25 litre/hour). In elderly patients this value is 19 litre/hour.
Elderly patients: 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 (see Precautions).
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.
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: Absorption: Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract. Due to the very small first pass effect (approx. 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 ensuring equivalent elimination. 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 unmetabolised form. 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 liver function impairment or renal insufficiency. Total clearance is approximately 15 litre/hour.
The elimination half-life in plasma is 10-12 hours.
The kinetics of bisoprolol are linear and independent of age.
Combination product: There has not been conducted any pharmacokinetic interaction study between the two compounds.
Even if such interaction exists, according to the results of bioequivalence study, the extent of this hypothetic interaction must be the same in case of taking Concor AMLO tablets, than in cases of taking the two compounds separately at the same dose levels as in the combination.
Toxicology: Preclinical safety data: In connection with amlodipine: Carcinogenesis: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about twice the maximum recommended human dose.
Mutagenesis: Mutagenicity studies revealed no drug related effects at either the gene or chromosome level.
Fertility: Standard fertility investigation revealed no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10mg/kg/day amlodipine (8 times the maximum recommended human dose of 10mg/day on a mg/m² basis). However, in a published investigation in which male rats were treated with amlodipine besilate for 30 days at dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
In connection with bisoprolol: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. During reproduction toxicology tests bisoprolol had no influence on fertility or general reproduction ability.
Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight increase) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) but was not teratogenic.