Mechanism of action
Cardio selective beta1-adrenergic blocker without internal sympathomimetic activity. It has a slight membrane stabilizing effect. It has antihypertensive, antianginal and antiarrhythmic effects. It lowers the automatism of the sinus node, reduces heart rate, slows AV conduction, reduces contractility and myocardial excitability, reduces cardiac output, reduces the need for oxygen in the myocardium. Suppresses the stimulating effect of catecholamines on the heart during physical and psycho-emotional stress.
Due to the peculiarities of the dosage form, a constant concentration of Metoprolol in the plasma is maintained and a stable clinical effect of the drug is maintained for 24 hours. Due to the absence of obvious peak concentrations in plasma, clinically, Betaloc ZOK is characterized by better beta1-selectivity compared to traditionally used pill forms of beta1-blockers. In addition, the potential risk of side effects observed at peak plasma concentrations of the drug, such as bradycardia or weakness in the legs when walking, is greatly reduced.
When used in moderate therapeutic doses, Betaloc ZOK has a less pronounced effect on the smooth muscles of the bronchi and peripheral arteries than non-selective beta-blockers. If necessary, Betaloc ZOK in combination with beta2-adrenomimetikami can be prescribed to patients with symptoms of obstruction of the lungs.
Betaloc ZOK to a lesser extent affects the secretion of insulin and carbohydrate metabolism and the activity of the cardiovascular system in conditions of hypoglycemia, compared with non-selective beta-blockers.
Clinical studies have shown that Betaloc ZOK may cause a slight increase in triglyceride levels and a decrease in the content of free fatty acids in the blood. In some cases, there was a slight decrease in the fraction of high-density lipoprotein (HDL), which is less pronounced than in the case of non-selective beta-blockers. However, one of the clinical studies showed a significant decrease in the level of total cholesterol in the blood serum during treatment with metoprolol for several years.
Quality of life during the period of treatment with the drug Betaloc ZOK does not deteriorate or improves. Improving the quality of life in the treatment with Bethalok ZOK is observed in patients after myocardial infarction, as well as in patients with idiopathic dilated cardiomyopathy.
In case of myocardial infarction, the drug helps to limit the zone of ischemia of the heart muscle and reduces the risk of arrhythmias, reduces the possibility of recurrence of myocardial infarction. With prolonged use, the drug reduces the incidence and risk of death in cardiovascular diseases (including IHD), including the risk of sudden death.
In the MERIT-HF, a survival study for chronic heart failure (NYHA class II-IV) with a reduced ejection fraction (<= 40%), which included 3,991 patients) Betaloc ZOK showed an increase in survival and a decrease in hospitalization. With long-term treatment, patients achieved a general improvement in health, a reduction in the severity of symptoms (according to NYHA classes). Also, therapy with the use of Betaloc ZOK showed an increase in the left ventricular ejection fraction, a decrease in the final systolic and end diastolic volumes of the left ventricle.
Suction and distribution
After oral administration, metoprolol is completely absorbed from the gastrointestinal tract. The bioavailability of metoprolol after a single dose of a single dose is approximately 50%. When using the dosage form with a slow release of metoprolol, its bioavailability is reduced by about 20-30% compared with conventional tablets. However, as tests have shown, this fact has no clinical significance, since for a sustained-release dosage form, the area under the HR curve is the same as for conventional tablets.
Associated with plasma proteins by about 5-10%.
Metabolism and excretion
Metoprolol is biotransformed in the liver by oxidation. The three main metabolites of metoprolol did not show a clinically significant beta-blocking effect.
About 95% of the ingested dose is excreted in the urine, of which 5% is unchanged.In some cases, the amount of the drug excreted in the urine in unchanged form, can reach 30%.
T1/2 averages 3.5 hours (from 1 to 9 hours). The total plasma clearance rate is approximately 1 l / min.
Pharmacokinetics in special clinical situations
In elderly patients, there are no significant changes in the pharmacokinetics of metoprolol compared with young patients.
Systemic bioavailability and excretion of metoprolol does not change in patients with reduced kidney function. The removal of metabolites in these patients, however, is reduced. Significant accumulation of metabolites was observed in patients with glomerular filtration rate of less than 5 ml / min. However, this accumulation of metabolites does not enhance the beta-blocking effect.
In patients with reduced liver function, the pharmacokinetics of metoprolol (due to the low degree of binding to plasma proteins) varies only slightly. However, in patients with severe liver cirrhosis or porto-caval shunts, the bioavailability of metoprolol may increase, and the total clearance may decrease. In patients with a porto-caval shunt, the total clearance was approximately 0.3 l / min, and the area under the concentration-time curve was 6 times larger than in healthy patients.
Indications and usage
- arterial hypertension: to reduce blood pressure and reduce the risk of cardiovascular and coronary complications, as well as reduce the risk of cardiovascular and coronary death (including sudden death);
- angina pectoris;
- stable chronic heart failure with impaired left ventricular systolic function (II, III-IV FK) (as an auxiliary therapy to the main treatment of heart failure);
- maintenance treatment after the acute phase of myocardial infarction (to reduce mortality and the frequency of recurrent infarction);
- heart rhythm disorders, incl. supraventricular tachycardia, as well as to reduce the frequency of ventricular contraction during atrial fibrillation and ventricular extrasystoles;
- functional disorders of cardiac activity, accompanied by tachycardia;
- prevention of migraine attacks.
At hypertension the initial dose is 50 mg 1 time / day. In the absence of a clinical effect, you can increase the dose to 100-200 mg 1 time / day or use Betaloc ZOK in combination with other antihypertensive drugs.
At angina pectoris The average therapeutic dose is 100-200 mg 1 time / day. If necessary, Betaloc ZOK can be used in combination with other antianginal drugs.
At stable chronic heart failure with impaired left ventricular systolic function It is possible to prescribe Betaloc to patients who have not had any episodes of exacerbation during the last 6 weeks and have not had any changes in the main therapy for the last 2 weeks. Beta-blocker therapy for heart failure can sometimes lead to a temporary worsening of the symptomatic picture.In some cases, it is possible to continue therapy or reduce the dose, and in some cases it may be necessary to discontinue the drug.
At stable chronic heart failure II f.k. The initial dose of the first 2 weeks is 25 mg 1 time / day. After 2 weeks, the dose can be increased to 50 mg 1 time / day, and then it can double every 2 weeks. The average therapeutic dose for long-term treatment is 200 mg / day.
At stable chronic heart failure III-IV FK The initial dose of the first 2 weeks is 12.5 mg 1 time / day. The dose is selected individually. During the period of increasing the dose, the patient should be under observation, since in some patients, the symptoms of heart failure may worsen. After 1-2 weeks, the dose may be increased to 25 mg 1 time / day, then after another 2 weeks, the dose may be increased to 50 mg 1 time / day. With good portability, you can double the dose every 2 weeks to reach the maximum dose of 200 mg 1 time / day.
In the case of hypotension and / or bradycardia, a reduction in concomitant therapy or a reduction in the dose of Betaloc AOC may be necessary. Hypotension at the beginning of therapy does not necessarily indicate that this dose of Betaloka ZOK will not be tolerated with further long-term treatment. However, the dose should not be increased until the condition stabilizes. You may also need to monitor kidney function.
For maintenance treatment after myocardial infarction the drug is prescribed at 200 mg / day. It was shown that as a result of long-term treatment of Betaloc ZOK at a dose of 200 mg, the risk of death (including sudden death) is reduced, the risk of recurrent heart attack (including patients with diabetes mellitus) is reduced.
At cardiac arrhythmias the drug is prescribed 100-200 mg 1 time / day.
At functional disorders of cardiac activity, accompanied by tachycardia, the dose is 100 mg 1 time / day, if necessary, the dose can be increased to 200 mg / day.
For migraine prevention prescribe Betaloc ZOK in a daily dose of 100-200 mg.
Betaloc ZOK is intended for daily intake of 1 time / day (preferably in the morning). Pill Betaloka ZOK should be swallowed with a liquid. Tablets can be divided in half, but should not be chewed or chopped.
When prescribing the drug to patients with renal impairment or persons old age no need to adjust the dosing regimen.
When prescribing the drug to patients with severe impaired liver function (for example, in patients with cirrhosis who have undergone bypass surgery) may require a decrease in its dose. Patients with cirrhosis of the liver do not need to adjust the dosage regimen.
The following criteria were used to assess the frequency of cases: “very often” - not less than 10%, “often” - 1-9.9%, “sometimes” - 0.1-0.9%, “rarely” - 0.01-0.09%, “very rarely” - less than 0.01%.
Since the cardiovascular system: often - bradycardia, postural disorders (very rarely accompanied by syncope), cooling of the extremities,feeling of heartbeat; sometimes - a temporary increase in symptoms of heart failure, AV block I degree, edema, pain in the heart; rarely - other conduction disorders, arrhythmias; very rarely - gangrene (in patients with severe peripheral circulatory disorders).
From the side of the central nervous system and peripheral nervous system: very often - fatigue; often - dizziness, headache; sometimes - paresthesia, muscle cramps, depression, decreased ability to concentrate, drowsiness or insomnia, nightmares; rarely - nervousness, anxiety, blurred vision, dryness and / or eye irritation, conjunctivitis; very rarely - memory impairment, amnesia, confusion, hallucinations, tinnitus, taste disturbances.
From the digestive system: often - nausea, abdominal pain, diarrhea, constipation; sometimes vomiting; rarely, dry mouth, changes in laboratory parameters of liver function; very rarely - hepatitis.
From the hemopoietic system: very rarely - thrombocytopenia.
On the part of the respiratory system: often - shortness of breath on exertion; sometimes bronchospasm; rarely - rhinitis.
Dermatological reactions: sometimes - a rash, dystrophic skin lesions, increased sweating; rarely - hair loss; very rarely - photosensitivity, exacerbation of psoriasis.
Other: sometimes - weight gain; rarely - impotence, arthralgia.
Betaloc ZOK is well tolerated; negative side effects are minor and are reversible.
- AV blockade II and III degree;
- chronic heart failure in the phase of decompensation (pulmonary edema, hypoperfusion syndrome or hypotension), ongoing or intermittent inotropic therapy aimed at stimulating beta receptors;
- clinically significant sinus bradycardia;
- cardiogenic shock;
- pronounced disorders of the peripheral arterial circulation;
- hypersensitivity to the drug or other beta-blockers.
Betaloc ZOK should not be prescribed to patients with suspected acute myocardial infarction with a heart rate less than 45 beats / min, PQ interval more than 0.24 s or systolic blood pressure less than 100 mm Hg.
During pregnancy and lactation (breastfeeding) Betaloc ZOK should be used only when absolutely necessary. It should be borne in mind that beta-adrenergic blockers may cause side effects (for example, bradycardia) in the fetus, newborns, or in breastfed babies. If a mother takes Betaloc ZOK in moderate therapeutic doses, the amount of metoprolol that a baby can get with breast milk is negligible compared to the dose needed to cause a beta-adreno-blocking effect in the baby.
If necessary, the appointment of Betaloc ZOK patients with bronchial asthma prescribe beta2agonists (in pill or aerosol form) as concomitant therapy.In cases where these patients are starting to take Betaloc ZOK, an increase in beta dose may be required.2agonists.
Patients with chronic heart failure should be in the stage of compensation and receive basic therapy both before and during treatment with Betaloc ZOK.
Very rarely, during the treatment with Betaloc ZOK, patients with conduction disorders may experience a worsening of the condition up to AV blockade. If bradycardia has developed during treatment, the dose of the drug should be reduced or the drug should be gradually discontinued.
In the period of use of the drug may increase the symptoms of peripheral arterial circulation, mainly due to a decrease in blood pressure.
If necessary, the appointment of Betaloc ZOK patients with pheochromocytoma should also be prescribed alpha-blockers.
Clinical research data on efficacy and safety in patients with severe stable heart failure (NYHA class IV) are limited. The treatment of such patients should be carried out by physicians with special knowledge and experience.
Patients with heart failure in combination with acute myocardial infarction and unstable angina pectoris were excluded from the studies on the basis of which indications for administration were determined. The efficacy and safety of the drug for this group of patients is not described. Use with unstable and decompensated heart failure is contraindicated.
Avoid abrupt discontinuation of the drug. Abrupt withdrawal of the drug is dangerous because of the possible risk of worsening of the course of heart failure, the occurrence of myocardial infarction and sudden death. The abolition of the drug should be carried out gradually for at least 2 weeks. The dose is reduced by 2 times at each stage. At the last stage, the dose is reduced to 12.5 mg. The last dose should be taken for at least 4 days before complete withdrawal of the drug. If symptoms recur, dose reduction should be delayed.
Patients taking beta-blockers should not be given iv verapamil-type Calcium channel blockers.
During the period of treatment with Betaloc ZOK, patients simultaneously receiving ganglioblockers, other beta-blockers (including in the form of eye drops) or MAO inhibitors should be under the close supervision of a physician.
Patients taking both Betaloc ZOK and oral hypoglycemic drugs may need a dose adjustment of the latter.
If surgical intervention is necessary, the anesthesiologist should be warned about the therapy being conducted in order to choose a remedy for anesthesia with minimal negative inotropic effect, however, it is not recommended to cancel the drug before the operation.
In cases where the patient simultaneously with the drug Betaloc ZOK gets clonidine, and this treatment must be interrupted, metoprolol should be canceled a few days before the withdrawal of clonidine.
It should be borne in mind that in patients taking beta-blockers, anaphylactic shock is more severe.
Use in pediatrics
Experience with the drug Betaloc ZOK in children is limited.
Influence on ability to drive motor transport and control mechanisms
Due to the likelihood of dizziness or weakness, the question of the possibility of practicing potentially hazardous activities requiring increased attention and speed of psychomotor reactions should be addressed after evaluating the patient's individual response to the drug.
Symptoms: possible pronounced decrease in blood pressure, sinus bradycardia, AV block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness up to coma, nausea, vomiting, cyanosis. Drinking alcohol, taking antihypertensive drugs, quinidine or barbiturates can lead to a deterioration in the patient's condition. The first symptoms of overdose can occur within 20 min-2 h after taking the drug.
Treatment: reception of Activated carbon , if necessary, gastric lavage. In case of severe hypotension, bradycardia, or the threat of developing acute heart failure, beta should be given.1agonist in / in with an interval of 2-5 minutes or as an infusion to achieve a therapeutic effect. In the absence of selective beta1- agonist can be introduced into / in dopamine or atropine sulfate. In the absence of a therapeutic effect, sympathomimetics can be used (dobutamine or norepinephrine). Glucagon is also used in a dose of 1-10 mg.It may be necessary to use an artificial pacemaker. For relief of bronchospasm should be in / in to enter beta2agonist. It should be borne in mind that the doses of drugs required for symptomatic therapy of overdose are much higher than the therapeutic ones, since the b-receptors are in a bound state with a beta-blocker.
With simultaneous use of Betaloka ZOK and antiarrhythmic drugs (quinidine-like agents and amiodarone), negative inotropic and dromotropic effects may be enhanced.
With simultaneous use with Betaloc ZOK increases the cardiodepressive effect of the means for inhalation anesthesia.
With the simultaneous use of Betaloka ZOK with calcium antagonists (verapamil, diltiazem) or other antiarrhythmics, there is a decrease in the minute and stroke volume of the heart, heart rate. With the / in the introduction of Verapamil there is a threat of cardiac arrest.
With simultaneous use of Betaloc ZOK with drugs that are inducers or inhibitors of microsomal enzymes, it is possible to change the concentration of metoprolol in plasma. The concentration of metoprolol in plasma decreases when taking rifampicin, may increase when taking cimetidine, ethanol, hydralazine, serotonin reuptake inhibitors (paroxetine, Fluoxetine , sertraline).
With simultaneous use of Indomethacin and other drugs that inhibit prostaglandins synthetase, the antihypertensive effect of Betaloc ZOK may be reduced.
With the simultaneous use of Betaloka ZOK with calcium channel blockers, cardiac glycosides, reserpine, nitrates, clonidine increases the risk of arterial hypotension, bradycardia, AV blockade, may increase the negative inotropic action.
The drug should be stored at temperatures below 30 ° C.