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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 mandatory, Betaloc ZOK, in combination with a β2-agonist, may be given to patients with symptoms of obstructive pulmonary disease. When given together with a β2-agonist, Betaloc ZOK in therapeutic doses interferes less than non-selective β-blockers with the β2-mediated bronchodilation caused by the β2-agonist.
Betaloc ZOK gives an even plasma concentration time profile and effect (β1-blockade) over 24 hours in contrast to conventional tablet formulations of β1-selective blockers.
Due to the lack of pronounced peaks in plasma concentration, the clinical β1-selectivity is improved with the Betaloc ZOK 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.
Betaloc ZOK interferes less with insulin release and carbohydrate metabolism than do non-selective β-blockers.
Betaloc ZOK interferes much less with the cardiovascular response to hypoglycaemia than do non-selective β-blockers.
Short term studies have shown that Betaloc ZOK 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 Betaloc ZOK.
An improvement in quality of life has been observed after metoprolol treatment in patients after myocardial infarction.
Pharmacokinetics: Absorption and distribution: Betaloc ZOK 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, but 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 elimination half-life of metoprolol averages 3.5 hours. Thus, an even metoprolol plasma concentration is achieved over a dosage interval of 24 hours.
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.
Due to its low protein binding the pharmacokinetics of metoprolol is little 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.
