Logimax Mechanism of Action

Pharmacotherapeutic group: Calcium antagonists and β-blockers. ATC code: C07FB02.
Pharmacology: Pharmacodynamics: Felodipine/Metoprolol succinate (LOGIMAX) is an antihypertensive preparation consisting of a combination of felodipine, which is a calcium antagonist with a selective effect on pre-capillary resistance vessels, and metoprolol, which is a β₁-selective receptor blocker.
As a result of the mechanisms of action of the two substances complementing each other (felodipine reduces peripheral vascular resistance and metoprolol reduces cardiac output), a more pronounced antihypertensive effect is obtained than with either of the two drugs in monotherapy. With Felodipine/Metoprolol succinate (LOGIMAX) an even and effective lowering of blood pressure over the entire interval between doses (24 hours) is achieved.
Felodipine: Felodipine is a vascular selective calcium antagonist for the treatment of hypertension and stable angina pectoris. Felodipine is a dihydropyridine derivative and a racemate.
Felodipine acts by reducing peripheral vascular resistance, especially in arterioles. The electrical and contractile activity in the smooth muscle cells in the vessels is inhibited via an effect on the calcium channels in the cell membrane.
As a result of felodipine having a selective effect on smooth muscle in the arterioles, in therapeutic doses it has no negative inotropic effect on the heart and no clinically significant electrophysiological effect in the heart. Felodipine relaxes smooth muscle in the respiratory tract. Clinical experience has shown that felodipine has little effect on gastrointestinal motoricity. No clinically significant effect of felodipine on blood lipid values has been observed during long-term treatment. Nor has any clinically significant effect on metabolic control (HbA1c) been observed in patients with type II diabetes during 6 months of treatment.
Felodipine can generally also be given to patients who also have reduced left ventricular function who are being treated with the usual therapy, and to those who have asthma, diabetes, gout or hyperlipidemia.
Antihypertensive effect: Felodipine lowers arterial blood pressure by reducing peripheral vascular resistance. Treatment of hypertensive patients with felodipine produces a lowering of blood pressure in supine, seated and standing position, at rest and during exercise. Felodipine does not cause orthostatic hypotension, as the substance does not affect smooth muscle in the veins or adrenergic control mechanisms. The lowered blood pressure may initially result in a transient, reflectory increase in heart rate and cardiac output. The increase in heart rate is counteracted if felodipine is given in combination with β-blockers. The effect on blood pressure and total peripheral vascular resistance is correlated to the plasma concentration of felodipine. In steady state the effect lasts for the entire interval between doses, and produces a lowering of blood pressure for the whole day.
Treatment with felodipine produces a regression of left ventricular hypertrophy.
Felodipine has a natriuretic and diuretic but no kaliuretic effect. Tubular reabsorption of sodium and water is reduced, which may explain the absence of salt and fluid retention in patients. Felodipine reduces renal vascular resistance and increases renal perfusion. Glomerular filtration is not affected. Felodipine does not affect albumin excretion.
Metoprolol: Metoprolol is a β₁-selective receptor blocker, which means that metoprolol influences the cardiac β₁-receptors in lower doses than those required to influence β₂-receptors in peripheral vessels and bronchi.
Metoprolol is devoid of a β-stimulant effect and has little membrane-stimulating effect. β-receptor blockers have negative inotropic and chronotropic effects.
Treatment with metoprolol reduces the effect of catecholamines connected with physical and psychological stress and produces a lower heart rate, lower cardiac output and lower blood pressure. In stress states with increased secretion of adrenaline from the adrenals, metoprolol does not prevent the normal physiological vasodilatation. In therapeutic doses, metoprolol has less contractile effect on the bronchial musculature than non-selective β-blockers. This property makes it possible to treat patients with bronchial asthma or other pronounced obstructive pulmonary disease with metoprolol in combination with β₂-receptor stimulants. Metoprolol influences insulin secretion and carbohydrate metabolism to a lesser degree than non-selective β-blockers, and can therefore also be given to patients with diabetes mellitus. The cardiovascular reaction in hypoglycemia, e.g. tachycardia, is affected to a lesser degree by metoprolol, and the return of the blood sugar level to normal takes place more rapidly than with non-selective β-receptor blockers.
In hypertension metoprolol produces a marked lowering of blood pressure in both supine and standing position and during physical effort. Initially, treatment with metoprolol causes an increase in peripheral vascular resistance. During long-term treatment, however, the achieved lowering of blood pressure is attributed to reduced peripheral vascular resistance and an unchanged cardiac output. Metoprolol reduces the risk of cardiovascular death in men with moderate/severe hypertension. Disturbances of electrolyte balance do not occur.
Pharmacokinetics: Felodipine: Bioavailability is approx. 15% and is not influenced by concomitant food intake. The rate of absorption - but not the degree of absorption - is affected by concomitant food intake, which is why the maximum plasma concentration increases by approx. 65%. The peak plasma concentration is reached after 3-5 hours. Binding to plasma proteins is approximately 99%. The volume of distribution in steady state is 10 L/kg. The half-life of felodipine in the elimination phase is approx. 25 hours, and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. Clearance is on average 1200 mL/min. Reduced clearance in elderly patients and patients with impaired hepatic function leads to these having higher plasma concentrations of felodipine. However, age only partially explains the inter-individual variations in plasma concentration. Felodipine is metabolized in the liver, and all identified metabolites are devoid of vasodilator effects. Approx. 70% of a given dose is excreted as metabolites via the urine, the remainder in the feces. Less than 0.5 % of a given dose is excreted in unchanged form in the urine. Impaired renal function does not affect the plasma concentration of felodipine, but accumulation of inactive metabolites occurs. Felodipine is not eliminated by hemodialysis.
Metoprolol: Absorption after oral administration is complete, and the substance is absorbed along the entire gastrointestinal tract, also in the colon. The bioavailability of Metoprolol Succinate (Betazok) is 30-40%. Metoprolol is metabolized in the liver mainly by CYP2D6. Three main metabolites have been identified, but none with a β-blocking effect of clinical significance. Approx. 5% of metoprolol is excreted via the kidneys in unchanged form, the remainder of the dose in the form of metabolites.
Characteristics of combination products: On administration of Felodipine/Metoprolol succinate (LOGIMAX) the bioavailability of neither metoprolol nor felodipine is altered, compared with concomitant administration of metoprolol and felodipine. Absorption is not influenced by concomitant intake of food.
Toxicology: Preclinical safety data: Available studies concerning general toxicity, genotoxicity and carcinogenicity did not reveal any special risks for humans. In animal studies β-receptor blockers caused bradycardia in the fetuses. In several species calcium antagonists have caused embryotoxic and/or teratogenic effects, mainly in the form of distal skeletal malformations. In reproduction toxicology studies with felodipine, prolonged pregnancy and difficult parturition were observed in rats, and in rabbits poorer development of distal phalanges was seen (probably caused by reduced uteroplacental perfusion). These observations do not indicate direct teratogenic effects, but suggest secondary consequences of the pharmacodynamic effects of felodipine.