Pharmacological properties
Pharmacodynamics. betaloc. IV metoprolol therapy in myocardial infarction allows to reduce the severity of pain in the chest, reduce the frequency of atrial fibrillation and flutter. Early initiation of therapy (within 24 hours after the appearance of the first symptoms) allows to limit the development and spread of the myocardial infarction zone. Early initiation of therapy increases the benefits of treatment.
In paroxysmal atrial tachycardia and atrial fibrillation/flutter, there is a decrease in the frequency of contraction of the ventricles of the heart.
Metoprolol is a selective β 1 -receptor blocker, that is, it affects the β 1 -receptors of the heart at lower doses compared to those required to affect the β 2 -receptors of peripheral vessels and bronchi. With increasing doses of the drug, the β 1 -selectivity may decrease.
Metoprolol reduces the effect of catecholamines during physical and psycho-emotional stress, leads to a decrease in heart rate, reduces cardiac output, and also reduces elevated blood pressure. In stressful situations accompanied by increased release of adrenaline from the adrenal glands, metoprolol does not interfere with normal physiological vasodilation. In therapeutic doses, metoprolol has a less contractile effect on the muscles of the bronchi than non-selective β-blockers. This property allows for treatment with metoprolol in combination with β 2 -adrenoceptor stimulants in patients with bronchial asthma or other severe obstructive lung diseases. Metoprolol affects insulin release and carbohydrate metabolism to a lesser extent than non-selective β 2 -adrenoceptor agonists, and therefore it can also be used in patients with diabetes. Cardiovascular reactions to hypoglycemia, such as tachycardia, are less pronounced with metoprolol, and the return of blood glucose levels to normal values occurs more quickly than with non-selective β2-adrenoceptor blockers.
Betaloc ZOK. Metoprolol is a selective β 1 -adrenoreceptor blocker. Metoprolol affects the β 1 -receptors of the heart in lower doses than the doses required to affect the β 2 -receptors of peripheral vessels and bronchi. The selectivity of Betaloc ZOK is dose-dependent, since the maximum concentration in the blood plasma when using the sustained-release dosage form is significantly lower than when taking the same dose in the form of a regular tablet. A higher degree of β 1 -selectivity is achieved due to the dosage in the dosage form of ZOK.
Metoprolol has no beta-stimulating effect and exhibits a slight membrane-stimulating effect. β-receptor blockers have a negative inotropic and chronotropic effect.
Treatment with metoprolol reduces the effect of catecholamines on the heart during physical and psycho-emotional stress and leads to a decrease in heart rate, cardiac output, and also reduces elevated blood pressure. In stressful situations accompanied by increased release of adrenaline from the adrenal glands, metoprolol does not interfere with normal physiological vasodilation. In therapeutic doses, metoprolol has less effect on bronchial muscles than non-selective β-blockers. This property provides the conditions for the treatment of patients with bronchial asthma or other severe obstructive lung diseases with metoprolol in combination with β 2 -receptor stimulants. Metoprolol has a lesser effect on insulin release and carbohydrate metabolism than non-selective β-blockers, so it can also be prescribed to patients with diabetes. Metoprolol has less effect on the cardiovascular response to hypoglycemia, such as tachycardia, and the return of blood glucose levels to normal values occurs more quickly than with non-selective β-blockers.
In hypertension, Betaloc ZOK significantly reduces blood pressure for more than 24 hours in the supine and standing positions, as well as during physical exertion. At the beginning of treatment with metoprolol, an increase in total peripheral vascular resistance (OPSS) is observed. However, with prolonged treatment, a decrease in blood pressure may occur by reducing OPSS against the background of unchanged cardiac output.
In a 4-week study in 144 patients aged 6 to 16 years with hypertension, Betaloc ZOK at doses of 1 and 2 mg/kg reduced placebo-adjusted systolic blood pressure by 4-6 mm Hg. diastolic blood pressure showed a placebo-adjusted reduction of 5 mm Hg. diastolic blood pressure at higher doses, and a dose-dependent reduction in blood pressure at doses of 0.2, 1, and 2 mg/kg. There were no significant differences by age, Tanner Scale (Adolescent Physical Development Scale), or race.
Metoprolol reduces the risk of cardiovascular death in men with moderate/severe hypertension. No electrolyte disturbances were noted.
In addition, treatment with Betaloc ZOK has been shown to increase ejection fraction and reduce end-systolic and end-diastolic volumes of the left ventricle.
In tachyarrhythmias, the effect of increased sympatholytic activity is blocked, and this leads to a lower heart rate, primarily due to a decrease in automatic function in pacemaker cells, as well as due to a prolonged supraventricular conduction time. Metoprolol reduces the risk of recurrent infarction and death, especially sudden, after myocardial infarction.
Pharmacokinetics. Betaloc. Metoprolol is metabolized in the liver, mainly with the participation of CYP 2D6. Three main metabolites have been identified, each of which does not have any clinically significant beta-blocking effect. T ½ from blood plasma is 3-5 hours. Approximately 5% of metoprolol is excreted by the kidneys unchanged, the rest - in the form of metabolites.
Betaloc ZOK.
The Betaloc ZOK sustained-release tablet consists of microcapsules containing granules of metoprolol succinate, and each capsule is a separate unit of content. Each capsule is coated with a polymer membrane that controls the rate of drug release. The tablet quickly disintegrates upon contact with liquid, and then the capsules are distributed over a significant surface area of the digestive tract. The release does not depend on the pH of the surrounding fluid and continues at an almost constant rate for 20 hours. This dosage form provides a uniform concentration of metoprolol succinate in the blood plasma and a duration of action of 24 hours.
Betaloc ZOK is completely absorbed after oral administration, and the substance is absorbed throughout the digestive tract, as well as in the large intestine. The bioavailability of the drug Betaloc ZOK is 30-40%. Metoprolol is metabolized in the liver, mainly with the participation of CYP 2D6. 3 main metabolites have been identified, none of which has any clinically significant β-blocking effect. Approximately 5% of metoprolol is excreted by the kidneys in unchanged form, the rest in the form of metabolites.
The pharmacokinetics of metoprolol in children and adolescents (6-17 years) resemble those in adults. Oral clearance of metoprolol increases linearly with body weight.
Indication
Betaloc solution for injection. Treatment of tachyarrhythmia, in particular supraventricular tachyarrhythmia. Acute myocardial infarction. Early use of Betaloc to reduce the area of infarction and reduce the frequency of ventricular fibrillation. Reduction of pain symptoms, which may also reduce the need for opioid analgesics. Reduction of mortality in patients with acute myocardial infarction.
Betaloc ZOK. AH. Angina pectoris. Stable chronic heart failure with impaired left ventricular systolic function. Prevention of cardiac death and recurrent infarction after the acute phase of myocardial infarction. Cardiac arrhythmias, including supraventricular tachycardia, decreased ventricular rate in atrial fibrillation and ventricular extrasystoles. Functional disorders of cardiac activity accompanied by palpitations. Migraine prevention.
Application
Betaloc solution for injection
Parenteral administration of Betaloc should be carried out under the supervision of specially trained personnel in places where blood pressure measurement, ECG and resuscitation measures can be performed.
Supraventricular tachyarrhythmia. Initially, 5 mg (5 ml) should be administered intravenously at a rate of 1-2 mg/min. This dose may be repeated every 5 min until the desired effect is achieved. Usually, a total dose of 10-15 mg (10-15 ml) is sufficient. The recommended maximum dose for intravenous administration is 20 mg (20 ml).
Prevention and treatment of myocardial ischemia, tachyarrhythmia and pain in suspected or diagnosed myocardial infarction. Acute condition: the drug should be administered intravenously at a dose of 5 mg (5 ml). The dose of the drug can be repeated every 2 minutes; the maximum dose is 15 mg (15 ml). 15 minutes after the last injection, 50 mg of metoprolol tartrate should be administered orally every 6 hours for 48 hours. For long-term oral use, Betaloc tablets or Betaloc ZOK prolonged-release tablets should be prescribed.
The diluted solution for injection should be used within 12 hours.
Betaloc ZOK
Betaloc ZOK is used once a day, preferably in the morning. The prolonged-release tablets can be divided, but they should not be chewed or crushed. The tablets are washed down with at least 0.5 cups of liquid. Simultaneous food intake does not affect the bioavailability of the drug.
The dose is selected individually. To avoid the development of bradycardia, the dose of the drug should be adjusted. The following dosage is recommended.
Hypertension. 50-100 mg once a day. If a dose of 100 mg is insufficient to achieve a therapeutic effect, the drug can be combined with other antihypertensive drugs, preferably diuretics and dihydropyridine-type calcium antagonists, or the dose of the drug can be increased.
Add-on therapy to ACE inhibitor, diuretic and possibly digitalis therapy in stable symptomatic heart failure. Patients should have stable chronic heart failure without episodes of decompensation for at least 6 weeks and without significant changes in baseline therapy for the past 2 weeks.
Treatment of heart failure with β-adrenergic blockers may lead to temporary worsening of symptoms. In some cases, it is possible to continue therapy or reduce the dose of the drug, sometimes it may be necessary to cancel the drug. In patients with severe heart failure (IV functional class according to the NYHA classification), therapy with Betaloc ZOK should be initiated only by an experienced specialist.
Stable heart failure, functional class II. The recommended initial dose of Betaloc ZOK for the first 2 weeks is 25 mg once a day. After 2 weeks, the dose can be increased to 50 mg once a day, and then the dose can be doubled every 2 weeks. The target dose of Betaloc ZOK for long-term treatment is 200 mg once a day.
Stable heart failure, functional class III-IV. The recommended initial dose is 12.5 mg (half a 25 mg tablet) once a day. The dose of the drug is adjusted individually. During the period of increasing the dose, the patient should be under close medical supervision, since in some patients the symptoms of heart failure may worsen. After 1-2 weeks of taking Betaloc ZOK, the dose can be increased to 25 mg once a day. After 2 weeks, the dose can be increased to 50 mg once a day. Patients who tolerate high doses well can double the dose every 2 weeks until the maximum dose of 200 mg/day is reached.
In case of hypotension and/or bradycardia, it may be necessary to reduce the dose of the concomitant medication or of Betaloc ZOK. Hypotension at the beginning of therapy does not necessarily indicate that the dose of Betaloc ZOK needs to be reduced. However, the dose should not be increased until the patient's condition has stabilized. It may also be necessary to closely monitor renal function.
Cardiac arrhythmia. 100-200 mg once a day. If necessary, the dose can be increased.
Maintenance therapy after myocardial infarction. The recommended maintenance dose is 200 mg once daily.
Functional cardiac disorders accompanied by palpitations. 100 mg once a day. If necessary, the dose can be increased.
Migraine prevention: 100-200 mg once daily.
Renal impairment: Renal function has only a minor effect on the rate of drug elimination, so there is no need for dose adjustment in patients with renal impairment.
Hepatic impairment: Patients with cirrhosis can usually be given the same dose as patients with normal liver function. Only in cases of very severe hepatic impairment (e.g. in patients with a history of bypass surgery) should a dose reduction be considered.
Elderly patients: No dose adjustment is required.
Contraindication
Cardiogenic shock. sick sinus syndrome. AV block II and III degree. heart failure in the stage of decompensation (pulmonary edema, hypoperfusion or hypotension); prolonged or intermittent inotropic therapy aimed at stimulating β-blockers. symptomatic bradycardia or hypotension. untreated pheochromocytoma.
Metabolic acidosis. Metoprolol should not be prescribed to patients with suspected acute myocardial infarction with a heart rate of 45 beats / min, PQ interval of 0.24 s, systolic blood pressure of 100 mm Hg, AV block of the first degree and / or severe heart failure. Serious peripheral vascular disease with the threat of gangrene. Hypersensitivity to the components of the drug or other β-adrenoceptor blockers.
Betaloc. In the case of supraventricular tachyarrhythmia, Betaloc should not be prescribed to patients whose systolic blood pressure is 110 mm Hg.
Betaloc ZOK. In the presence of symptoms of heart failure, the patient's condition with repeated BP values of 100 mm Hg in the supine position should be re-evaluated before starting treatment.
Side effects
Adverse reactions, usually dose-related, occur in approximately 10% of patients. Adverse reactions associated with the use of metoprolol are listed below by system organ class and frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency unknown (cannot be estimated from the available data).
| Blood and lymphatic system disorders |
| rarely | thrombocytopenia |
| mental disorders |
| Not often | Depression, nightmares, sleep disturbances |
| rarely | Memory impairment, confusion, hallucinations, nervousness, anxiety |
| frequency unknown | Decreased concentration |
| From the central and peripheral nervous system |
| Very often | fatigue |
| often | Dizziness, headache |
| Not often | paresthesias |
| rarely | taste disturbance |
| frequency unknown | muscle cramps |
| From the organ of vision |
| rarely | Visual disturbances, dryness and/or irritation of the eyes |
| Symptoms resembling conjunctivitis |
| Hearing and balance disorders |
| rarely | Ringing in the ears |
| From the heart |
| often | Cold extremities, bradycardia, palpitations |
| Not often | Transient worsening of heart failure symptoms, cardiogenic shock in patients with acute myocardial infarction |
| rarely | Prolongation of AV conduction, cardiac arrhythmia |
| frequency unknown | Gangrene in patients with severe peripheral vascular disease |
| Respiratory system |
| often | Shortness of breath during physical activity |
| Not often | Bronchospasm in patients with bronchial asthma or obstructive disorders |
| frequency unknown | rhinitis |
| Gastrointestinal tract |
| often | Abdominal pain, nausea, vomiting, diarrhea, constipation |
| frequency unknown | Dry mouth |
| Hepatobiliary disorders |
| rarely | Increased transaminase levels |
| frequency unknown | hepatitis |
| Skin and subcutaneous tissue disorders |
| Not often | Skin hypersensitivity reactions |
| rarely | Psoriasis exacerbation, photosensitivity, hyperhidrosis, hair loss |
| Musculoskeletal and connective tissue disorders |
| frequency unknown | arthralgia |
| Reproductive system and breast disorders |
| rarely | Reversible libido dysfunction |
| general disorders |
| Not often | Chest pain, swelling, weight gain |
|
Betaloc when administered intravenously may in some cases cause a clinically significant decrease in blood pressure.
Also, when using metoprolol, insomnia, drowsiness, amnesia, first-degree AV block, worsening of existing AV block, postural disorders (very rarely with syncope), Raynaud's phenomenon, increased symptoms of intermittent claudication, rash (in the form of psoriatiform urticaria and dystrophic skin lesions), impotence / sexual dysfunction, precardial pain, the appearance of antinuclear antibodies (not associated with systemic lupus erythematosus), and injection site reactions may occur.
Special instructions
Patients receiving treatment with β-adrenergic blockers should not receive intravenous verapamil.
Metoprolol may cause peripheral arterial circulatory disorders such as claudication. Special attention should be paid to patients with severe renal impairment, serious acute conditions and patients receiving combination therapy with digitalis drugs.
In patients with Prinzmetal's angina, the frequency and severity of angina attacks may increase as a result of alpha-receptor-mediated coronary vasoconstriction. Therefore, nonselective β-blockers should not be prescribed to such patients. Selective β 1 -adrenoceptor blockers should be used with caution.
In the treatment of patients with bronchial asthma or other obstructive pulmonary diseases, adequate bronchodilator therapy should be administered simultaneously. It may be necessary to increase the dose of β2-adrenergic stimulators.
Treatment with metoprolol may affect carbohydrate metabolism or mask the development of hypoglycemia, although this risk is lower than with non-selective β-adrenergic blockers.
Very rarely, the condition of patients with moderate AV conduction disturbances may worsen (possibly to AV block).
Therapy with β-adrenergic blockers may reduce the effectiveness of stopping the anaphylactic reaction. Treatment with adrenaline in usual doses does not always lead to the expected therapeutic effect.
Patients with pheochromocytoma should be simultaneously prescribed α-adrenergic blockers when treated with Betaloc / Betaloc ZOK.
Patients with symptomatic heart failure accompanied by acute myocardial infarction and unstable angina were excluded from the study, which established the possibility of using the drug in heart failure. Therefore, the effectiveness and safety of treatment in acute myocardial infarction accompanied by heart failure has not been documented. Betaloc / Betaloc ZOK is contraindicated in unstable, uncompensated heart failure.
In case of surgical intervention, it is necessary to warn the anesthesiologist that the patient is taking Betaloc / Betaloc ZOK. It is not recommended to stop treatment with β-blockers in patients who are scheduled for surgery. If the cancellation of metoprolol is considered necessary, it should, if possible, occur at least 48 hours before general anesthesia. Urgent initiation of the use of metoprolol in high doses in patients who have undergone non-cardiac surgery should be avoided, as this is associated with the development of bradycardia, hypotension and stroke, including fatal outcome in patients with cardiovascular risk factors.
However, some patients have
