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 nonselective 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 nonselective 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 hrs 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 adverse reactions, e.g. bradycardia and leg fatigue is reduced.
Betaloc ZOK interferes less with insulin release and carbohydrate metabolism than do nonselective β-blockers.
Betaloc ZOK interferes much less with the cardiovascular response to hypoglycaemia than do nonselective 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 nonselective β-blockers. However, a significant reduction in total serum cholesterol levels has been demonstrated after metoprolol treatment in a study conducted over several years.
Quality of life is maintained, uncompromised or improved during treatment with Betaloc ZOK.
An improvement in the quality of life has been observed after metoprolol treatment in patients after myocardial infarction (MI).
In MERIT-HF, a survival study comprising 3991 patients with chronic heart failure [new york heart association (NYHA) II-IV] and decreased ejection fraction (≤0.4), Betaloc ZOK has been shown to increase survival and to reduce the number of hospitalisations. In long-term treatment, the patients experience a general improvement of symptoms (NYHA class and Overall Treatment Evaluation score).
In addition, it has been shown that Betaloc ZOK therapy increases the ejection fraction, and reduces the left ventricular end systolic and end diastolic volumes.
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 prolonged-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 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 (3) 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 hrs (extremes: 1 hour and 9 hours). The total clearance rate is approximately 1 litre/min.
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 glomerular filtration rate (GFR) of <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 less likely affected by decreased liver function. However, in patients with severe liver cirrhosis and a portacaval shunt, the bioavailability of metoprolol may increase and total clearance may be reduced. Patients with a portacaval anastomosis had a total clearance of approximately 0.3 L/min and area under the plasma concentration-time curve (AUC) values up to 6 times higher than in healthy subjects.