Betazok 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.
Metoprolol CR (BETAZOK) gives an even plasma concentration time profile and effect (β₁-blockade) over 24 hours in contrast to conventional tablet formulations of β₁-selective blockers including metoprolol tartrate formulations.
Due to the lack of pronounced peaks in plasma concentration, the clinical β₁-selectivity is improved with the Metoprolol CR (BETAZOK) formulation when compared to conventional tablet formulations of β₁-selective blockers. Furthermore, the potential risk for peak plasma concentration related side-effects, such as bradycardia and leg fatigue is reduced. When required, Metoprolol CR (BETAZOK), 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 CR (BETAZOK) in therapeutic doses interferes less than non-selective β-blockers with the β₂-mediated broncho-dilation caused by the β₂-agonist.
Metoprolol CR (BETAZOK) interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Metoprolol CR (BETAZOK) interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that Metoprolol CR (BETAZOK) 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 CR (BETAZOK). An improvement in quality of life has been observed after metoprolol treatment in patients after myocardial infarction. Furthermore, Metoprolol CR (BETAZOK) has been shown to improve Quality of Life in patients with chronic heart failure.
Effect in hypertension: Metoprolol CR (BETAZOK) 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 144 paediatric patients (6 to 16 years of age) with essential hypertension, Metoprolol CR (BETAZOK) has been shown in a 4-week study to reduce placebo-corrected systolic blood pressure for the 1.0 and 2.0 mg/kg doses (4 to 6 mmHg). For diastolic blood pressure, there was a placebo-corrected reduction for the 2.0 mg/kg dose (5 mmHg) and a dose-dependent reduction for the dose range 0.2, 1.0 and 2.0 mg/kg. No apparent differences in blood pressure reduction were observed based on age, Tanner stage, or race.
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 CR (BETAZOK) 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 CR (BETAZOK) is suitable for the treatment of functional heart disorders with palpitations.
Effect on migraine: Metoprolol CR (BETAZOK) is suitable for prophylactic treatment of migraine.
23.75 mg: Effect in chronic heart failure: In patients with symptoms of heart failure (NYHA II-IV) and decreased ejection fraction (≤0.40) Metoprolol CR (BETAZOK) has been shown to increase survival and to reduce the number of hospitalisations due to worsening heart failure. In addition, Metoprolol CR (BETAZOK) therapy has increased ejection fraction, reduced left ventricular end systolic and end diastolic volumes, improved NYHA functional class and improved Quality of Life.
In the MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestion Heart Failure) study treatment with metoprolol CR added to standard treatment with ACE inhibitors and diuretics in patients with decreased LVEF and symptoms of mild to severe chronic heart failure reduced: All cause mortality by 34% (p=0.0062 (adjusted); p=0.00009 (nominal)).
Combined endpoint of all cause mortality, and all cause hospitalisation (time to first event) by 19% (p=0.00012).
Combined endpoint of all cause mortality, and hospitalisation due to worsening heart failure (time to first event) by 31% (p=<0.00001).
Combined endpoint of death and heart transplantation (time to first event) by 32% (p=0.0002).
Cardiovascular death by 38% (p=0.00003).
Sudden death by 41% (p=0.0002).
Death from worsening heart failure by 49% (p=0.0023).
The pooled incidence of cardiac death and non-fatal acute MI by 39% (p=<0.00001).
Combined endpoint of all cause mortality, hospitalisation due to worsening heart failure, and emergency room (ER) visit due to worsening heart failure (time to first event) by 32% (p=<0.00001).
The number of hospitalisations due to worsening heart failure by 30% and the number of hospitalisations due to cardiovascular (CV) causes by 15% (p=0.0003).
Pharmacokinetics: Absorption and distribution: Metoprolol CR (BETAZOK) is completely absorbed after oral administration. Owing to an extensive first-pass effect, the systemic bioavailability of metoprolol from a single oral dose is approximately 50%. The bioavailability is reduced by about 20-30% for the controlled-release preparation compared with a conventional tablet. However, this has been demonstrated to be of no significance for clinical efficacy, since the area under the effect curve (AUEC) for heart rate is the same as with conventional tablets. The plasma protein binding of metoprolol is low, approximately 5-10%.
The controlled-release tablet consists of several hundred beads of metoprolol succinate. Each bead is coated with a polymeric membrane, which controls the rate of metoprolol release.
The tablet disintegrates rapidly after intake whereby the beads are dispersed in the gastrointestinal tract and release metoprolol continuously for about 20 hours. The elimination half-life of metoprolol averages 3.5 hours (see Metabolism and elimination). Thus, an even metoprolol plasma concentration is achieved over a dosage interval of 24 hours. The release rate is independent of physiological factors such as pH, food and peristalsis.
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 younger 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.
The pharmacokinetic profile of metoprolol in paediatric hypertensive patients aged 6-17 years is similar to the pharmacokinetics described previously in adults. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight.
Toxicology: Preclinical safety data: No findings of relevance.