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Pharmacotherapeutic group: Beta blocking agents, selective, and other antihypertensives. ATC code: C07FB07.
Pharmacology: Pharmacodynamics: Mechanism of action of amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined, but amlodipine reduces total ischaemic burden by the following two actions: Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
Pharmacodynamic effects: In patients with hypertension, once daily dosing 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 amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
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 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 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, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. The bioavailability of amlodipine is not affected by food intake.
Biotransformation/elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Hepatic impairment: Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
Elderly population: 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 studied.
Bisoprolol: Absorption: Bisoprolol is absorbed almost completely (>90%) 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. 50% is metabolised by the liver to inactive metabolites, which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in 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 l/h.
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 exist, - according to the results of bioequivalence study - the extent of this hypothetic interaction must be the same in case of taking Concor AM, than in case of taking the two compounds separately at the same dose levels as in the combination.
Toxicology: Preclinical safety data: In connection with amlodipine: Reproductive toxicology: Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Impairment of fertility: There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a 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.
Carcinogenesis, mutagenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of a carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
*Based on patient weight of 50 kg.
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.
