Betaloc Zok Mechanism of Action

Pharmacotherapeutic group: Beta-receptor blocker, selective. ATC code: C07A B02.
Pharmacology: Pharmacodynamics: Metoprolol is a beta₁-selective receptor blocker, i.e. metoprolol affects the beta₁-receptors of the heart in lower doses than needed to affect beta2-receptors in peripheral vessels and bronchi. The selectivity for Betaloc ZOK is dose dependent, but, as the peak plasma concentration for this dosage form is significantly lower compared to the same dose given as ordinary tablets, a higher degree of beta₁-selectivity is obtained with the ZOC-dosage form.
Metoprolol has no beta-stimulating effect and has little membrane- stimulating effect. Beta-receptor blockers have negative inotropic and chronotropic effect.
Metoprolol therapy reduces the effect of catecholamines in association with physical and psychic strain and gives lower heart rate, cardiac output and blood pressure. In stress situations with an increased release of adrenaline from the adrenal glands, metoprolol does not prevent the normal physiological vascular dilation. In therapeutic doses, metoprolol has less contractile effect on the bronchial muscles than non- selective beta-blockers. This property enables treatment of patients with bronchial asthma or other pronounced obstructive lung diseases with metoprolol in combination with beta₂-receptor stimulants. Metoprolol influences insulin release and carbohydrate metabolism to less extent than non-selective beta-blockers and therefore it can also be given to patients with diabetes mellitus. The cardiovascular reaction in hypoglycaemia, e.g. tachycardia, is less influenced by metoprolol and the return of blood sugar level to normal is faster than for non-selective beta-receptor blockers.
In hypertension, Betaloc ZOK lowers the blood pressure significantly for more than 24 hours both in lying and standing position as well as during exercise. In treatment with metoprolol an increase in the peripheral vascular resistance is observed initially. In long-term treatment, however, the obtained lowering in blood pressure may be due to reduced peripheral vascular resistance and unchanged cardiac output.
Paediatric population: In a four-week study with 144 patients between 6 and 16 years old with essential hypertension, doses of 1.0 and 2.0 mg/kg of Betaloc ZOK decreased placebo-corrected systolic blood pressure by 4-6 mmHg. Diastolic blood pressure showed a placebo-corrected decrease for the higher dose with 5 mmHg and a dose-dependent decrease for 0.2, 1.0 and 2.0 mg/kg. No noticeable differences between ages, Tanner scale (adolescent physical development) or race.
Metoprolol reduces the risk of cardiovascular-related deaths in men with moderate/serious hypertension. There is no disturbance in the electrolyte balance.
Effect in chronic heart failure: In MERIT-HF, a survival study comprising 3,991 patients with heart failure (NYHA II-IV) and decreased ejection fraction (≤ 0.40), 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 (New York Heart Association 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.
In tachyarrhythmias the effect of increased sympatholytic activity is blocked and this gives a lower heart rate primarily by reduced automatisation in the pacemaker cells, but also through a prolonged supraventricular conduction time. Metoprolol reduces the risk of reinfarction and cardiac death, especially sudden death after myocardial infarction.
Pharmacokinetics: The Betaloc ZOK prolonged release tablet consists of micro-encapsulated beads of metoprolol succinate, and each bead is a separate depot unit. Each bead is coated with a polymeric membrane, which controls the rate of drug release. The tablet disintegrates rapidly in contact with fluid whereby the beads are dispersed over a large surface in the gastrointestinal tract. The release is independent of the pH of the surrounding fluid and goes on with an almost constant rate for about 20 hours. The dosage form gives an even plasma concentration and effect duration over 24 hours.
The absorption is complete after oral administration and the substance is absorbed along the whole gastrointestinal tract, also in colon. The bioavailability of Betaloc ZOK is 30-40%. Metoprolol is metabolised in the liver mainly by CYP2D6. Three main metabolites have been identified, though none has a beta-blocking effect of clinical importance. Metoprolol is excreted to approximately 5% in unchanged form via the kidneys, the remaining dose as metabolites.
The pharmacokinetics of metoprolol in children and young adults, 6 - 17 years, resembles that of adults. Clearance of orally given metoprolol (CL/F) increased with linear relation to the bodyweight.
Toxicology: Preclinical safety data: Metoprolol has been tested clinically to a very large extent.