Betaloc Mechanism of Action

ATC-code: C07A B02.
Pharmacology: Pharmacodynamics: Metoprolol is a β₁-selective β-blocker, i.e. it blocks β₁-receptors at doses much lower than those needed to block β₂-receptors.
Metoprolol has an insignificant membrane-stabilising effect and does not display partial agonistic activity.
Metoprolol reduces or inhibits the agonistic effect on the heart of catecholamines (which are released during physical and mental stress). This means that the usual increase in heart rate, cardiac output, cardiac contractility and blood pressure, produced by the acute increase in catecholamines, is reduced by metoprolol. During high endogenous adrenaline levels metoprolol interferes much less with blood pressure control than non-selective β-blockers. When required, metoprolol, in combination with a β₂-agonist, may be given to patients with symptoms of obstructive pulmonary disease. When given together with a β₂-agonist, metoprolol in therapeutic doses interferes less than non-selective β-blockers with the β₂-mediated bronchodilation caused by the β₂-agonist.
Metoprolol interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Metoprolol interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that metoprolol may cause a slight increase in triglycerides and a decrease in free fatty acids in the blood. In some cases, a small decrease in the high density lipoproteins (HDL) fraction has been observed, although to a lesser extent than that following non-selective β-blockers. However, a significant reduction in total serum cholesterol levels has been demonstrated after metoprolol treatment in one study conducted over several years.
Quality of Life is maintained uncompromised or improved during treatment with metoprolol.
An improvement in Quality of Life has been observed after metoprolol treatment in patients after myocardial infarction.
Effect in hypertension: Metoprolol lowers elevated blood pressure both in the standing and lying position. A short-lasting (a few hours) and clinically insignificant increase in peripheral resistance may be observed after the institution of metoprolol treatment. During long-term treatment total peripheral resistance may be reduced, due to reversal of hypertrophy in arterial resistance vessels. Long-term antihypertensive therapy with metoprolol has also been shown to reduce left ventricular hypertrophy and to improve left ventricular diastolic function and left ventricular filling.
In men with mild to moderate hypertension metoprolol has been shown to reduce the risk of death from cardiovascular disease mainly due to a reduced risk for sudden cardiovascular death, to reduce the risk of fatal and non-fatal myocardial infarction and for stroke.
Effect on angina pectoris: In patients with angina pectoris metoprolol has been shown to reduce the frequency, duration and severity of both angina attacks and silent ischemic episodes and to increase the physical working capacity.
Effect on cardiac rhythm: In cases of supraventricular tachycardia or atrial fibrillation, and in the presence of ventricular extrasystoles, metoprolol slows the ventricular rate and reduces ventricular extrasystoles.
Effect on myocardial infarction: In patients with suspected or confirmed myocardial infarction metoprolol lowers mortality mainly due to a reduction in the risk of sudden death. This effect is presumed to partly be due to the prevention of ventricular fibrillation.
The anti-fibrillatory effect is believed to be due to a dual mechanism: a vagal effect within the blood-brain barrier beneficially influencing electrical stability of the heart, and a sympathetic direct cardiac anti-ischemic effect beneficially influencing contractility, heart rate and blood pressure. For both early and late intervention the reduction in mortality is also present in high risk patients with previous cardiovascular disease; and in patients with diabetes mellitus.
Metoprolol has also been shown to reduce the risk of non-fatal myocardial re-infarction.
Effect on heart disorders with palpitations: Metoprolol is suitable for the treatment of functional heart disorders with palpitations.
Effect on migraine: Metoprolol is suitable for prophylactic treatment of migraine.
Effect on hyperthyroidism: Metoprolol reduces the clinical manifestations in hyperthyroidism and can therefore be given as supplementary medication.
Pharmacokinetics: Absorption and distribution: Metoprolol is completely absorbed after oral administration. Within the therapeutic dosage range the plasma concentrations rise linearly in relation to the size of the dose. Peak plasma concentrations are attained after approx 1.5 - 2 hours. Although the plasma profiles exhibit wide inter-subject variability, they show good reproducibility within each individual.
Owing to an extensive first-pass effect, the systemic bioavailability of metoprolol from a single oral dose is approximately 50%. Upon repeated administration, the systemically available portion of the dose increases to approx 70%. Ingestion together with food may raise the systemic availability of an oral dose by approx 30-40%. The plasma protein binding of metoprolol is low, approximately 5-10%.
Metabolism and elimination: Metoprolol undergoes oxidative metabolism in the liver primarily by the CYP2D6 isoenzyme. Three main metabolites have been identified, though none of them have a β-blocking effect of clinical importance.
As a rule, over 95% of an oral dose can be recovered in the urine. About 5% of the given dose is excreted in the urine in unchanged form, this figure rising up to 30% in isolated cases. The elimination half-life of metoprolol in plasma averages 3.5 hours (extremes: 1 and 9 hours). The total clearance rate is approximately 1 litre/minute.
Elderly show no significant changes in the pharmacokinetics of metoprolol as compared with young persons. The systemic bioavailability and elimination of metoprolol is unchanged in patients with reduced renal function. The excretion of metabolites, however, is reduced. Significant accumulation of metabolites was observed in patients with a glomerulus filtration rate (GFR) of less than 5 mL/min. This accumulation of metabolites, however, does not increase the β-blockade.
The pharmacokinetics of metoprolol is minimally affected by decreased liver function. However, in patients with severe liver cirrhosis and a portacaval shunt the bioavailability of metoprolol may increase and the total clearance may be reduced. Patients with a portacaval anastomosis had a total clearance of approximately 0.3 litres/min and area under the plasma concentration-time curve (AUC) values up to 6 times higher than in healthy subjects.
Toxicology: Preclinical safety data: No findings of any relevance.