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Pharmacotherapeutic group: Beta blocking agents, selective, and other antihypertensives. ATC code: C07FB07.
Pharmacology: Pharmacodynamics: Mechanism of action of Amlodipine: Amlodine 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 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 tablets 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 beta1-selective adrenoreceptor-blocking agent devoid of intrinsic sympathomimetic activity (ISA) and without relevant membrane stabilising activity.
It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, Bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-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. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing. 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.
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.
Renal impairment: The pharmacokinetics of Amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
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%.
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: A pharmacokinetic interaction study demonstrated no interaction between the two compounds.
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 10 mg/kg/day Amlodipine (8 times the maximum recommended human dose of 10 mg/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 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 test 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.
