Metoprolol, 30 pcs., 100 mg, extended-release film-coated tablets

Pharmacodynamics and pharmacokinetics

The drug has antiarrhythmic, antianginal and hypotensive effects. The drug does not have internal SMA and does not have a membrane-stabilizing effect.

The hypotensive effect is due to a decrease in the synthesis of renin, monooxygenase, inhibition of the activity of the renin-angiotensin system and the central nervous system. The drug can lower blood pressure during stress and physical exertion at rest.

The antianginal effect is ensured by a decrease in pulse rate, as well as a decrease in the need for oxygen in myocardial tissue. Long-term use of the medication increases exercise tolerance and reduces the severity of angina attacks and their frequency. As a result of eliminating arrhythmogenic factors (arterial hypertension, increased cAMP content, tachycardia, increased activity of the sympathetic nervous system), an antiarrhythmic effect is achieved.

For thyrotoxicosis, heart diseases of functional origin, sinus tachycardia , atrial fibrillation, supraventricular tachycardia, Metoprolol allows you to restore sinus rhythm and reduce heart rate. The drug prevents the formation of migraines.

Average therapeutic dosages of metoprolol, unlike other beta-blockers, have a less pronounced effect on the organs in which beta-2-blockers are located (uterus, bronchi, smooth muscle tissue of peripheral arteries, skeletal muscles, pancreas) and on carbohydrate metabolism.

Long-term use of the medication leads to a decrease in blood cholesterol levels.

Metoprolol tartrate. Application in clinical practice

A.A. ZATEISHIKOVA

, Candidate of Medical Sciences,
City Clinical Hospital No. 51 of the Moscow Department of Health
It is difficult to imagine an area of ​​cardiology where beta-blockers would not be used. Doctors now have a huge variety of drugs in their arsenal, differing from each other in pharmacodynamic and pharmacokinetic properties. Beta-blockers, being catecholamine antagonists, inhibit their chronotropic, inotropic and vasoconstrictor effects, which is what their use in clinical practice is based on.

The main effects of beta-blockers are an anti-ischemic effect (as a result of a decrease in myocardial oxygen demand against the background of a decrease in heart rate, a decrease in myocardial contractility and blood pressure on the one hand, and an improvement in myocardial blood supply against the background of prolongation of diastole and a decrease in LV end-diastolic pressure - with another), antihypertensive effect provided by a decrease in cardiac output (negative chrono- and inotropic effect), influence on the RAAS system due to blockade of β1-adrenergic receptors of the juxtaglomerular apparatus of the kidneys, which leads to a decrease in the secretion of renin, the formation of angiotensin II and aldosterone; blockade of presynaptic β-adrenergic receptors, inhibition of the release of norepinephrine from sympathetic nerve endings; a decrease in vasomotor activity of the central nervous system and restructuring of the baroreceptor mechanisms of the aortic arch and carotid sinus, an antiarrhythmic effect manifested in a decrease in heart rate, a decrease in the spontaneous activation of ectopic pacemakers, and a slowdown in conduction in the AV node [1]. The effectiveness of beta blockers in congestive heart failure is associated both with their effect on the renin-angiotensin-aldosterone system and with changes in the regulation of beta receptors and normalization of the Gi protein in cardiomyocytes [2].

Based on accumulated data on effectiveness and safety, beta blockers are approved by the FDA for the treatment of arterial hypertension, various forms of coronary heart disease, heart failure, and some supraventricular arrhythmias [3].

One of the most popular and well-studied drugs is metoprolol.

Metoprolol is a representative of the group of lipophilic beta-blockers, a selective blocker of β1-adrenergic receptors, without intrinsic sympathomimetic activity [4]. In medications, metoprolol is in the form of salts that ensure solubility in water. Metoprolol tartrate has the greatest solubility (approximately 700 mg per ml of water at 37 ° C). The drug is almost completely absorbed from the stomach, the maximum concentration in plasma is achieved 1-2 hours after administration, the half-life is on average 3.5 hours. Bioavailability is 50-70%, stable concentration in the blood is achieved when taken 2 times a day [5 ].

I would like to note that it was metoprolol tartrate that was used in most of the large clinical randomized studies, the results of which became the basis for clinical recommendations and opened new horizons in the treatment of severe cardiac patients.

Arterial hypertension

The pharmacodynamic features of metoprolol tartrate make it possible to successfully use it both as an emergency drug and for permanent therapy for arterial hypertension.

The use of the drug Egilok for the relief of uncomplicated hypertensive crisis at a dose of 50-100 mg led to a decrease in blood pressure from the initial one by an average of 35% - systolic and 15% - diastolic with the onset of the maximum effect 20-30 minutes after sublingual or oral administration [6] .

A study of the use of metoprolol as monotherapy for the treatment of arterial hypertension of I-II degrees showed that taking metoprolol twice a day provides an effective reduction in blood pressure, a decrease in blood pressure variability, without having a negative effect on the lipid and carbohydrate composition of the blood for 12 weeks . reception. Also, no side effects were found that led to the need to discontinue the drug [7].

The prognostic impact of metoprolol in the treatment of hypertension was demonstrated in the large Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study, which included 3,234 male patients aged 40–64 years with diastolic hypertension (diastolic blood pressure greater than 100 mm Hg). The aim of the project was to evaluate the effect of metoprolol therapy on the incidence of cardiovascular events (sudden death and myocardial infarction). The comparison group (1,635 patients) received thiazide diuretic therapy. The results of the study showed the unconditional advantage of metoprolol in preventing coronary death, fatal and non-fatal myocardial infarction. Interestingly, the 225 patients who experienced cardiovascular events during follow-up (111 in the metoprolol group and 144 in the diuretic group, RR = 0.76) did not differ in either baseline characteristics or the achieved antihypertensive effect from patients with a favorable forecast. This fact gave grounds for the assertion that metoprolol has an additional protective effect, in addition to the antihypertensive one [8].

Cardiac ischemia

Beta blockers, including metoprolol, are certainly recommended for the treatment of stable angina. During treatment with beta blockers, exercise tolerance increases, the number of angina attacks and episodes of silent myocardial ischemia decreases. In addition, the effectiveness of this group of drugs for the prevention of myocardial infarction and cardiovascular mortality has been proven [9–11].

In the HINT study (Holland Interuniversity Nifedipine/metoprolol Trial), the use of metoprolol tartrate in patients with unstable angina was accompanied by a significant reduction in recurrent anginal attacks and the development of myocardial infarction [12].

A number of studies are devoted to the use of metoprolol in the acute and subacute period of myocardial infarction.

The results of the large double-blind, placebo-controlled MIAMI (Metoprolol in acute myocardial infarction) study, published in 1985, which involved 5,778 patients with suspected acute myocardial infarction, demonstrated the positive effect of metoprolol therapy (200 mg) started as early as possible after admission. per day after fractional intravenous administration) on the early prognosis of patients with myocardial infarction. We assessed mortality and the incidence of complications (ventricular fibrillation, supraventricular arrhythmias) within 15 days. Myocardial infarction was confirmed in 4,127 patients included in the study. There was no significant difference in mortality rates between the treatment and placebo groups. However, among patients at high risk of an adverse outcome (approximately 30% of included patients), a 29% reduction in mortality was noted. The most significant effect was in the groups of patients with confirmed MI, for whom treatment was started within the first 7 hours of admission. The incidence of ventricular fibrillation was slightly lower, although not significantly, in the metoprolol group; supraventricular arrhythmias, the need for the use of cardiac glycosides, antiarrhythmics, and narcotic drugs were significantly lower in the treatment group [13].

Patients aged 40–74 years admitted to hospital with suspected acute myocardial infarction within 48 hours of the onset of symptoms were included in the Göteborg Metoprolol Trial. Shortly after admission, patients were randomized to metoprolol or placebo groups. After fractional administration of 15 mg of metoprolol intravenously, they switched to oral administration of metoprolol tartrate at a dose of 200 mg per day. After 3 months randomized treatment, most patients took open-label metoprolol. Mortality during the first 3 months was assessed. and year. Of the 1,395 patients in the study, 262 (19%) had evidence of heart failure before randomization. Mortality in the metoprolol treatment group was significantly lower than during the first 3 months. observation (10 vs. 19%, p = 0.036) and during the year (14 vs. 27%, p = 0.0099) [14].

The results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study did not reveal a convincing advantage of early administration of intravenous metoprolol over delayed initiation of oral metoprolol in the context of long-term prognosis and preservation of left ventricular systolic function. Of the 1,434 patients with MI who received thrombolytic therapy, half began therapy with metoprolol on the first day with intravenous administration, and the rest received metoprolol only on the 6th day at a dose of 50 mg twice a day, with a further increase in the daily dose to 200 mg. In the so-called group early initiation of therapy, episodes of ischemia and recurrent myocardial infarction were significantly less frequently recorded during the first week [15].

RIMA (Rimodellamento Infarto Miocardico Acuto), a study using captopril or metoprolol or their combination on the first day of acute myocardial infarction, aimed to evaluate the effect of the above treatment regimens on prognosis over 6 months. Treatment with metoprolol was associated with a decrease in the number of percutaneous revascularization procedures and fewer side effects [16].

The beneficial effect of metoprolol on prognosis (mortality and development of recurrent myocardial infarction) over 3 years was recorded in the SMT study (Stockholm Metoprolol Trial). In this double-blind, placebo-controlled study, two groups were formed: placebo (147 people) and metoprolol 100 mg 2 times a day (154 people). Randomization was carried out from 11 to 18 days from the onset of MI, observation lasted 36 months. Results demonstrated reductions in all-cause mortality, recurrent myocardial infarction, sudden cardiac death, and cerebrovascular events and coronary artery bypass grafting in the treatment group. The most pronounced effect was observed in patients with widespread myocardial infarction [17].

There is evidence that the use of metoprolol on the first day in patients with ST-segment elevation myocardial infarction undergoing primary coronary artery angioplasty is associated with a smaller infarct area and a larger LV ejection fraction, determined by MRI on days 5-7 of MI [18].

Heart failure

The first major study on the use of beta blockers in patients with systolic heart failure, which radically changed the attitude towards the use of beta blockers in heart failure, was conducted with metoprolol. Metoprolol in Dilated Cardiomyopathy Trial Study Group (MDC) included 383 patients with chronic heart failure due to dilated cardiopathy with a left ventricular ejection fraction of less than 40%. The vast majority of patients had functional class III-IV heart failure. For 2-7 days, metoprolol was prescribed at a test dose of 5 mg 2 times a day. 96% of patients who satisfactorily tolerated this stage were then randomized to metoprolol or placebo groups. In the treatment group, the dose of the drug was gradually increased to 100-150 mg per day. The primary endpoints of this study were major deterioration in clinical status (need for heart transplantation) and death. After 12 months the incidence of primary endpoints was 34% lower in the metoprolol group than in the placebo group (2 and 19 patients, respectively, experienced deterioration, 23 and 19 patients, respectively, died). In the treatment group, the change in left ventricular ejection fraction after a year of observation compared to the baseline was significantly more pronounced, as well as the degree of reduction in wedge pressure (5 versus 2 mm in the placebo group). Patients receiving metoprolol had significantly higher exercise tolerance at the end of the observation period [19].

The assumption of a beneficial effect of metoprolol on the prognosis of patients with heart failure due to coronary artery disease was confirmed in a small double-blind, placebo-controlled randomized trial. Treatment with metoprolol at the maximum tolerated dose (average 87 mg/day) in patients with ischemic cardiomyopathy, systolic dysfunction (LVEF ≤ 40%) for six months was associated with a significant reduction in the frequency of hospitalizations, increased exercise tolerance, a decrease in the functional class of heart failure, an increase in LV ejection fraction [20].

The positive effect of metoprolol tartrate therapy on the systolic and diastolic functions of the left ventricle in patients with heart failure was also confirmed in the work of Swedish scientists. It is noteworthy that the study included patients with mild and moderate heart failure (II-III NYHA), LV ejection fraction of no more than 40% with cardiomyopathy of both ischemic (93 people) and non-ischemic (72 people) origin, who were not constantly taking beta - adrenergic blockers. All patients were randomized to receive placebo or metoprolol tartrate with a target dose of 50 mg three times a day, the dose of the drug was increased over 6 weeks. to the maximum tolerated. The treatment period lasted 6 months. Ejection fraction and cardiac volumes were measured using steady-state radionuclide angiography at rest and during exercise (bicycle ergometry). The average age of patients is about 56 years. The average ejection fraction is 29%. After 6 months in patients receiving metoprolol, the LV ejection fraction was significantly higher both at rest and during exercise than in patients in the placebo group. LV end-diastolic and end-systolic volumes at rest and during submaximal exercise decreased significantly in the group treated with metoprolol and did not change in those treated with placebo. Moreover, the differences were significant both in patients with ischemic cardiomyopathy and in patients with DCM [21]. Similar results of 6-month metoprolol therapy on left ventricular remodeling and ejection fraction were obtained in another study in which various echocardiographic parameters were used to assess LV function [22].

Atrial fibrillation

The effectiveness of immediate-release metoprolol for heart rate control in patients with persistent atrial fibrillation has not been studied in large, randomized, placebo-controlled trials. However, data from small observations [23], as well as the results of systematization of available information on the use of beta-blockers in patients with a permanent form of atrial fibrillation [24], allow us to recommend the use of metoprolol in this category of patients.

Being a highly selective β1-adrenergic receptor blocker, metoprolol can be used to treat cardiovascular diseases in patients with concomitant chronic pulmonary pathology, including COPD and bronchial asthma. There is ample evidence of the beneficial effect of beta blockers on the prognosis of such patients, even with exacerbation of COPD [25, 26].

It is generally accepted that the use of selective beta blockers is associated with hypoperfusion of skeletal muscles, which, in turn, provides a negative effect of beta blockers on some metabolic processes, including the risk of developing diabetes mellitus, the development of insulin resistance, weight gain, and adverse effects. shifts in the lipid profile [24]. In this regard, metoprolol as a selective β1-blocker is used as a comparison drug in the study of potentially metabolically neutral drugs (carvedilol, nebivolol). It is noteworthy that the results of this type of study demonstrate very little, if any, negative effect of metoprolol on key parameters [27]. For example, in the CAMELIA study, conducted to identify the advantages of carvedilol over metoprolol, which included 320 patients with arterial hypertension and increased body weight over 6 months. After treatment with metoprolol, no significant changes in biochemical parameters were noted [28].

Summarizing the above data, we can say that, despite the emergence of new drugs from the group of beta-blockers, which have certain advantages, metoprolol tartrate firmly occupies its rightful place in the treatment of major diseases of the cardiovascular system due to its favorable efficacy/safety profile, as well as strong evidence based on the beneficial effect of the drug on the prognosis of cardiac patients.

Literature

1. Oleynikova G.L. Some aspects of the use of bisoprolol in cardiovascular pathology. Russian Medical Journal, 2009. 17. 8: 614-616. 2. Maksimov M.L. Rational choice of β-blockers in the treatment of chronic heart failure. RFK, 2007. 1. 3. Helfand M, Peterson K, Christensen V, Dana T, Thakurta S. Drug Class Review: Beta Adrenergic Blockers: Final Report Update 4 [Internet]. Portland (OR): Oregon Health & Science University. 2009 Jul. 4. Benfield P, Clissold SP, Brogden RN. Metoprolol: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischemic heart disease and related cardiovascular disorders. Drugs, 1986. 31(5): 376-429. 5. Johnsson G, Jordo L, Lundborg P, et al. Plasma levels and pharmacological effects of metoprolol administered as controlled release (durules) and ordinary tablets in healthy volunteers. Int J Clin Pharmacol Ther Toxicol 1980. 18(7): 292-97. 6. Makhatova A.R., Beisenbaeva A.K., Dyusupova Z.B. Use of the β-blocker egilok in emergency settings. Bulletin of modern clinical medicine, 2010. Appendix 1. volume 3. 7. Podzolkov V.I., Isaykina O.Yu., Samoilenko V.V., Makolkin V.I. Clinical effectiveness of the beta-blocker metoprolol in patients with hypertension. Russian Journal of Cardiology, 2000. 4. 8. Wikstrand J, Warnold I, Tuomilehto J, et al. Metoprolol versus thiazide diuretics in hypertension: morbidity results from the MAPHY Study. Hypertension, 1991. 17: 579-88. 9. Tereshchenko S.N., Kositsina I.V., Jaiani N.A. Do we all know about the features of metoprolol in the treatment of coronary heart disease? Cardiology, 2005. 45(4): 98-101. 10. Rehnqvist N, Hjemdahl P, Billing E. et al Effects of metoprolol versus verapamil in patients with stable angina pectoris. The angina prognosis study in Stockholm (APSIS). Eur Heart J 1996. 1776–89.89. 11. Heidenreich PA1, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, Hlatky MA Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA, 1999. 26. 281(20): 1927-36. 12. Tijssen JG1, Lubsen J. Early treatment of unstable angina with nifedipine and metoprolol—the HINT trial. J Cardiovasc Pharmacol 1988. 12. Suppl 1:S71-7. 13. Metoprolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial. The MIAMI Trial Research Group. Eur Heart J 1985 6(3): 199-226. 14. Herlitz J1, Waagstein F, Lindqvist J, Swedberg K, Hjalmarson A. Effect of metoprolol on the prognosis for patients with suspected acute myocardial infarction and indirect signs of congestive heart failure (a subgroup analysis of the Göteborg Metoprolol Trial). Am J Cardiol 1997 13 80(9B): 40J-44J. 15. Roberts R1, Rogers WJ, Mueller HS, Lambrew CT, Diver DJ, Smith HC, Willerson JT, Knatterud GL, Forman S, Passamani E, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation, 1991. 83(2): 422-37. 16. Coletta C, Ricci R, Ceci V, Seccareccia F, Rulli F, Mazzuca V, Putini RL, Salustri A, Bottero G, Pasquale M. Effects of early treatment with captopril and metoprolol singly or together on six-month mortality and morbidity after acute myocardial infarction. Results of the RIMA (Rimodellamento Infarto Miocardico Acuto) study. The RIMA researchers. G Ital Cardiol., 1999. 29(2): 115-24. 17. Olsson G, Rehnqvist N, Sjögren A, Erhardt L, Lundman T. Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity. J Am Coll Cardiol., 1985. 5(6): 1428-37. 18. Ibanez B1, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L, Mateos A, Fernández-Ortiz A, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation, 2013. 1. 128(14): 1495-503. 19. Waagstein F1, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC). Trial Study Group. Lancet, 1993. 11. 342(8885): 1441-6. 20. Fisher ML1, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol., 1994. 15. 23(4): 943-50. 21. Waagstein F1, Strömblad O, Andersson B, Böhm M, Darius M, Delius W, Goss F, Osterziel KJ, Sigmund M, Trenkwalder SP, Wahlqvist I. Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy. Eur J Heart Fail 2003. 5(5): 679-91. 22. Grüner Sveälv B1, Täng MS, Waagstein F, Andersson B. Pronounced improvement in systolic and diastolic ventricular long axis function after treatment with metoprolol. European Journal of Heart, 2007. 9, Issue 6-7: 678–683. 23. Shubik Yu.V., Medvedev M.M., Rivin A.E., Kuchumov V.S. Control of heart rate and correction of the psycho-emotional status of patients with persistent atrial fibrillation: impact on the quality of life. Vestn aritmol, 2003. 24. James J DiNicolantonio, Hassan Fares, Asfandyar K Niazi, Saurav Chatterjee, Fabrizio D'Ascenzo, Enrico Cerrato, Giuseppe Biondi-Zoccai, Carl J Lavie, David S Bell, and James H O'Keefe. β-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature. Open Heart. 2015. 2(1). 25. Dransfield MT1, Rowe SM, Johnson JE, Bailey WC, Gerald LB. Use of beta blockers and the risk of death in hospitalized patients with acute exacerbations of COPD. Thorax, 2008. 63(4): 301-5. Epub 2007 Oct 19. 26. Angeloni E1, Melina G, Roscitano A, Refice S, Capuano F, Lechiancole A, Comito C, Benedetto U, Sinatra R. β-Blockers improve survival of patients with chronic obstructive pulmonary disease after coronary artery bypass grafting. Ann Thorac Surg., 2013. 95(2): 525-31. doi: 10.1016/j.athoracsur.2012.07.080. Epub 2012 Oct 4. 27. Bakris GL1, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT Jr, Oakes R, Lukas MA, Anderson KM, Bell DS; GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA, 2004. 10. 292(18): 2227-36. 28. Martsevich S.Yu., Kutishenko N.P., Shilova E.V. Comparison of the metabolic effects of carvedilol and metoprolol in patients with arterial hypertension and overweight/obesity. Research CAMELIA. Rational pharmacotherapy in cardiology, 2009. 2. volume 5.

Indications for use of Metoprolol

The medicine is used for myocardial infarction , unstable angina , exertional angina , coronary , arterial hypertension arterial hypertension crisis .

The drug is used for rhythm disturbances: supraventricular arrhythmia , ventricular form of arrhythmia, sinus tachycardia , atrial tachycardia, atrial flutter, atrial fibrillation , ventricular extrasystole .

The drug is used for thyrotoxicosis (in complex therapy), for tremor (senile, essential forms), for migraines, withdrawal syndrome , akathisia when taking antipsychotics, and for anxiety.

Release form of Metoprolol

Metoprolol is available in tablet form for systemic treatment. The main substance is metoprolol tartrate, which can be contained in the amount of 25 mg, 50 mg or 100 mg in one tablet. Auxiliary components:

• magnesium stearate;
• silica;
• sodium carboxymethyl starch;
• microcrystalline cellulose.

The drug belongs to the cardioselective beta-blockers.

Contraindications

Metoprolol is not prescribed for 2-3 degree atrioventricular block, cardiogenic shock , intolerance to the active substance, acute form of heart failure , and arterial hypotension , Prinzmetal's angina , breastfeeding, in the acute period of myocardial infarction, simultaneous use of an MAO inhibitor, with intravenous infusion of Verapamil.

With metabolic acidosis , myasthenia gravis, diabetes mellitus, liver failure, pheochromocytoma, chronic renal failure, COPD (chronic obstructive bronchitis , emphysema ), with bronchial asthma, obliterating disease of peripheral vessels, during pregnancy, thyrotoxicosis, psoriasis, depression, in pediatric practice, persons In elderly patients, the medicine is prescribed with caution.

Side effects

Nervous system: slower speed of motor and mental reactions, weakness, headaches, increased fatigue, paresthesia in the extremities, convulsions, tremors, drowsiness, attention disorders, anxiety, insomnia, myasthenia gravis, hallucinations, memory impairment, confusion, “nightmare” dreams, asthenia.

Sense organs: eye pain, decreased vision, conjunctivitis, dry eyes, decreased tear production.

Cardiovascular system: orthostatic hypotension , loss of consciousness, dizziness, drop in blood pressure, sinus bradycardia, swelling, decreased myocardial contractility, cardialgia , myocardial conduction disorders, manifestation of vasospasm, CHF, rarely worsening of impaired atrioventricular conduction is observed.

Digestive tract: changes in taste, disturbances in liver function (cholestasis, darkening of urine, yellowing of the skin and sclera).

Skin: photodermatosis , psoriasis-like skin reactions, exacerbation of psoriasis, skin rashes, exanthema, reversible form of alopecia, increased sweating.

Respiratory system: bronchospasm, nasal congestion, shortness of breath.

Endocrine system: hypoglycemia (in insulin-requiring diabetes mellitus), hyperglycemia (in persons with non-insulin-dependent diabetes mellitus), hypothyroid state. Possible development of rash, itching, allergies, thrombocytopenia, hyperbilirubinemia, agranulocytosis.

The effect of Metoprolol on the fetus: hypoglycemia, intrauterine growth retardation, bradycardia.

The drug can cause decreased potency, libido, weight gain, and joint pain. Abrupt cessation of taking the drug causes the development of “withdrawal syndrome”.

Side effects of Metoprolol

Taking Metoprolol in rare cases can cause a number of side effects:

• increased fatigue;
• drowsiness;
• decreased concentration;
• sleep disorders.

Less common are negative effects on the organ of vision: dry tear duct, dry eye syndrome and pain.

From the digestive tract - taste disturbance and decreased liver function. In addition, skin reactions in the form of photodermatosis also occur. If the patient has a manifestation of psoriasis on the skin, the affected area may increase or enter an acute stage. In some patients, the intensity of sweating increases.

From the respiratory system - nasal congestion, bronchospasm or shortness of breath appears.

Metoprolol tablets, instructions for use (Method and dosage)

The medicine is taken orally. Tablets should not be divided in half, chewed, or broken. The average dosage for arterial hypertension is 100-150 mg for 1-2 doses per day.

Angina: 2-3 times a day 50 mg.

Thyrotoxicosis, hyperkinetic cardiac syndrome, tachyarrhythmia: 1-2 times a day, 50 mg.

For secondary prevention of myocardial infarction, 200 mg of metoprolol is indicated.

For the prevention of migraine, 100-200 mg per day is prescribed for 2-4 doses.

In case of paroxysmal supraventricular tachycardia, in order to stop the attack, it is administered parenterally under inpatient observation.

In case of acute myocardial infarction, Metoprolol is administered immediately after hospitalization of the patient; it is necessary to monitor the level of blood pressure, pulse, ECG, and atrioventricular conduction.

For elderly people, therapy begins with 50 mg per day. In case of pathology of the hepatic system, dosage adjustment is not carried out (it is preferable to prescribe drugs that are not metabolized in the hepatic system).

Instructions for use of Metoprolol Ratiopharm and Metoprolol Acri are similar.

Metoprolol in the pharmacotherapy of coronary heart disease and concomitant pathologies

Coronary heart disease (CHD) is the most common reason for adults visiting medical institutions among all cardiovascular diseases in our country. The frequency of this pathology reaches 28% of cases. According to the Russian register of acute coronary syndrome, in almost half of patients with acute coronary insufficiency, the first manifestation of coronary artery disease is myocardial infarction. Therefore, it can be assumed that only 40–50% of all patients with coronary artery disease are aware of the presence of the disease and receive appropriate treatment, while in 50–60% of cases the disease remains unrecognized [1]. This actualizes the topic of clinical examinations, screening identification of risk factors and adequate treatment of pathological processes leading to vascular accident. Prescribing complete drug treatment can improve the quality of life and significantly reduce the incidence of complications and mortality among people with chronic forms of coronary artery disease. Recommendation documents in recent years systematize medications taking into account the strength of the evidence base in terms of the effect on pain and/or exercise tolerance in patients with angina pectoris. A special role is given to drugs that can improve prognosis and reduce the risk of disability and serious cardiovascular events.

Antianginal drugs that can reduce the frequency, duration and intensity of angina attacks include nitrates, calcium antagonists, and beta-blockers [2]. According to modern clinical guidelines for the treatment of stable coronary artery disease, angina pectoris is an indication for the prescription of beta-blockers [3]. Traditionally, in cardiology, preference is given to selective beta-blockers. Metoprolol tartrate has been used as an antianginal agent for more than twenty years. The mechanism of the antianginal action of the drug has been studied in detail. The “Pharmacodynamics” section of the instructions for the state register of metoprolol tartrate drugs emphasizes the ability of the drug to reduce myocardial oxygen demand by reducing systemic blood pressure, heart rate and myocardial contractility. By lengthening diastole when taking metoprolol, blood supply and oxygen uptake by the myocardium with impaired blood flow are improved. Therefore, for exertional angina, the drug reduces the number, duration and severity of attacks, as well as asymptomatic manifestations of ischemia, and improves the patient’s physical performance [4]. If symptoms are not well controlled, a combination of beta-blockers with dihydropyridine calcium antagonists is recommended [5,6].

In addition to its antianginal properties, metoprolol is a typical antihypertensive drug. The results of a large-scale meta-analysis by M.Law et al indicate that beta-blockers as initial therapy prevent coronary outcomes [7]. In arterial hypertension (AH), metoprolol reduces blood pressure (BP) by slowing the rhythm. The long-term antihypertensive effect is associated with a gradual decrease in total peripheral resistance. In hypertension, long-term use of the drug leads to a statistically significant decrease in the mass of the left ventricle and an improvement in its diastolic function [4]. The greatest effectiveness of beta-blockers was detected when used by patients with concomitant cardiac pathology, in particular, coronary artery disease and hypertension. The combination of coronary artery disease and hypertension is an almost daily clinical situation in the real practice of internists working both in hospitals and in outpatient settings. Among outpatients with cardiovascular diseases, the incidence of the combination of hypertension and ischemic heart disease reaches 67%. This result is known from the data of the Russian PREMIER study, conducted in 14 cities of Russia with the participation of more than 14,000 patients [8]. Similar data were published in the REACH (Reduction of Atherothrombosis for Continued Health) registry. Arterial hypertension in patients with coronary artery disease occurred in more than 80% of cases [9].

The recommended target blood pressure level for patients with hypertension and coronary artery disease is less than 140/90 mm Hg. Art. [10]. In this regard, drugs with two indications are of particular interest: arterial hypertension and coronary heart disease. Of the listed antianginal drugs, only calcium antagonists (dihydro- and non-dihydropyridine) and beta-blockers have such indications. It should be noted that the doses of the same drug in the treatment of different nosologies may differ, despite the common pathogenetic processes. Thus, in accordance with the instructions of the State Register of Medicines (GRLS), for hypertension, the initial dose of metoprolol tartrate is 25-50 mg twice a day, if necessary, the daily dose is gradually increased to 100-200 mg/day or another antihypertensive drug is added [4 ]. The usual daily dose after myocardial infarction is 100-200 mg/day, divided into 2 doses. Concomitant renal pathology in patients does not require a change in dosage regimen for any of the indicated nosologies. Due to the low binding of metoprolol to plasma proteins (5-10%), dose reduction in liver cirrhosis is also not recommended and may only be required in severe liver failure [4]. For angina pectoris, the initial dose of metoprolol tartrate is 25-50 mg, it can be taken two to three times a day with a gradual increase to 200 mg/day.

Blood pressure control in hypertensive patients with coronary artery disease is important, since the risk of developing recurrent coronary events largely depends on blood pressure levels [11]. However, it is necessary to remember the threshold value of DBP level is 70-75 mmHg. Art., in which a further decrease may be accompanied by a worsening of the disease.

In hypertensive patients who have suffered a myocardial infarction, early administration of beta-blockers reduces the risk of recurrent infarction and death [10-12]. A meta-analysis by Law MR showed that beta-blockers are highly effective in preventing cardiovascular events in patients with a recent myocardial infarction [7]. The results of the metoprolol study (Göteborg Metoprolol Trial) also indicate the high effectiveness of the drug in patients after myocardial infarction: the use of metoprolol for 90 days reduced mortality by 36%. This effect persisted regardless of age, previous infarction, or history of beta-blocker use. After three months, all patients were recommended to continue taking the drug, and the difference in mortality between the placebo group and the control group remained. Fewer episodes of ventricular fibrillation were recorded with metoprolol than in the placebo group (six versus 17 patients). In the metoprolol group, lidocaine, furosemide and analgesics were used less frequently [13].

In myocardial infarction, metoprolol is known to reduce mortality rates by reducing the risk of sudden death. This effect is primarily associated with the prevention of episodes of ventricular fibrillation. A reduction in mortality can be observed in both the early and late phases of myocardial infarction, in high-risk patients and patients with diabetes mellitus [4].

The delayed positive effect may be associated not only with the specific properties of beta-blockers. A significant role is assumed to be played by factors such as limiting the damaging effects of hyperactivation of the sympathetic nervous system, blocking the release of free fatty acids from adipose tissue caused by catecholamines, reducing oxidative stress, and reducing insulin resistance [14].

The effectiveness of long-term use of beta-blockers after myocardial infarction has been shown in a large number of studies [15]. However, these studies were generally conducted before the introduction of modern reperfusion techniques and drug therapy. However, in the absence of contraindications, beta-blockers are considered recommended for all patients who have suffered a myocardial infarction. They are most effective in patients with reduced left ventricular ejection fraction [15].

In addition to hypertension, which makes a dominant contribution to the statistics of death from coronary artery disease, there is another strategic component of hemodynamics - heart rate (HR), which is also influenced by beta-blockers and calcium antagonists, excluding the subgroup of dihydropyridines. Taking into account the contraindications to non-dihydropyridine calcium antagonists (verapamil, diltiazem) in chronic heart failure (CHF) and a significant amount of positive evidence confirming the effects of suppressing sympathetic activation, beta-blockers are becoming the dominant alternative in the combination of hypertension, tachyforms of arrhythmias and CHF. The fact of the relationship between high heart rate and mortality and other cardiovascular outcomes has been proven in a number of observational and epidemiological studies [16-20].

The results of the Framingham study showed an increase in both overall and cardiovascular mortality in patients with arterial hypertension, regardless of gender and age, with increasing heart rate. It is known that for every 40 beats per minute, the odds ratio of death from complications of cardiovascular disease was 1.68 and 1.70, and death from any cause was 2.14 and 2.18, respectively, for men and women [21]. Heart rate is the target parameter for exertional angina. The target heart rate, according to the results of a number of studies, was 55-60 beats per minute [22,23]. Cordero A et al [24] conducted an observational, multicenter study that included almost three hundred thousand patients with coronary artery disease. Compared with other drugs (including non-dihydropyridine calcium antagonists), patients receiving beta-blockers (atenolol, bisoprolol, metoprolol) had a significantly lower heart rate (67.2 versus 73.0 beats/min, P <0.01). Metoprolol, independently of other factors (OR: 1.29, 95% CI: 1.04 -1618; P = 0.04), was associated with heart rate control. At the same time, the authors concluded that in everyday practice, heart rate control in patients with coronary artery disease is insufficient.

A number of similar studies have attempted to determine whether patients achieve chronotropic therapeutic goals in real-life clinical practice. According to international registries, the proportion of patients who reached a heart rate of 55-60 beats/min does not exceed 22%. In twenty centers in 6 cities of the Russian Federation, the heart rate of patients (average age 64 ± 10 years) with angina pectoris FC I - III, taking a beta-blocker for at least two months at a constant dose for 4 weeks before inclusion in the program, was assessed. The proportion of patients with achieved target heart rate was 15.5% [25]. Similar data were obtained in a study designed to determine the adequacy of beta-blockers in outpatient settings in patients with angina pectoris [26]. Over 6 months, 2226 outpatients with stable coronary artery disease and a resting heart rate of more than 60 beats/min were registered. Overall, 45.4% of patients with CAD were not on beta blocker therapy. It is interesting to note that the heart rate values ​​in men were lower than in women. A multiple regression analysis was performed that included beta blocker use as an independent variable. It was found that non-use of beta blockers, female gender (OR 2.55), NYHA classes III-IV CHF (OR 1.62), smoking (OR 0.89) and increased body mass index (OR 0.14) are independent determinants of heart rate in peace. It was proven that the lack of use of beta-blockers (OR 3.35) was the dominant factor in the increase in heart rate, independent of other parameters. Heart rate in patients treated with beta-blockers was significantly lower than in patients not treated (73.6 ± 10.0 vs. 77.1 ± 10.4, P < 0.0001), although it often did not reach values ​​less than 60 beats/min.

In 2014, data from the CLARIFY prospective registry were published [24]. Data from 32,914 patients with angina, myocardial infarction and heart failure from 45 countries were analyzed; 75% of these patients were receiving beta blockers and had a heart rate of 68 ± 11 beats/min. Rates of beta blocker use varied by geographic region (87% to 67%). The main drugs used were bisoprolol (34%), metoprolol tartrate (16%) or succinate (13%), atenolol (15%) and carvedilol (12%); the mean doses were 49%, 76%, 35%, 53%, and 45% of the maximum doses, respectively. Patients, regardless of gender, over the age of 65 years were more likely to receive beta blockers than patients ≥ 75 years (P < 0.0001). Patients with heart rate ≤ 60 bpm received more intense beta blocker regimens than patients with heart rate ≥ 70 bpm (P < 0.0001). Patients with angina, previous myocardial infarction, heart failure, and hypertension were more likely to receive beta blockers (all P <0.0001), while patients with peripheral arterial disease and asthma/COPD were less likely to receive beta blockers (P <0.0001). The authors emphasize that heart rate is not well controlled in many patients, despite clinical recommendations for the management of CAD.

The choice of a beta-blocker within a class is based on the absence of intrinsic sympathomimetic activity, prolonged action, and a convincing evidence base for effectiveness and tolerability [2,10-12]. In addition, it is important that the instructions for the drug contain a wide range of comorbid conditions pathogenetically associated with IHD. The possibility of using one drug for several indications significantly reduces the risks of negative pharmacological reactions of both pharmacokinetic and pharmacodynamic nature. The ability of an antianginal drug to have a negative bathmotropic effect is especially relevant, because IHD is often accompanied by ectopic cardiac activity. Unlike nebivolol, betaxolol, carvedilol, bisoprolol, metoprolol has indications related to rhythm generation disorders [4]. In particular, metoprolol tartrate is indicated for supraventricular tachycardia, ventricular extrasystole, as well as for functional disorders of cardiac activity accompanied by tachycardia. According to the instructions, the drug is prescribed from 25-50 mg/day with a possible dose increase to 200 mg/day. In the “Standard of emergency medical care for tachycardias and tachyarrhythmias” [27], metoprolol is the only selective beta-blocker proposed for the care of adults with ventricular and supraventricular tachycardia, atrial fibrillation and flutter.

Therefore, current guidelines recommend beta blockers along with calcium antagonists as first-line treatment to control angina symptoms and heart rate. There is a significant dissonance between the proven facts about the need for drug reduction of rhythm in patients with coronary artery disease and real clinical practice. Often, patients either do not receive beta-blockers or take doses that are insufficient to maintain target heart rates. It is necessary to remember the relevance of the recommendations of experts from the European Society of Cardiology, focusing on the priority of prescribing beta-blockers. The choice of a selective beta-blocker metoprolol with a long-term mechanism of action and the presence of indications in the instructions related to tachyforms of arrhythmias and/or hypertension will contribute to both the secondary prevention of complications of coronary artery disease and the leveling of angina attacks, which will improve the quality of life of patients.

Literature

1. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Montalescot G., Sechtem U., Achenbach S. et al. ESC guidelines on the management of stable coronary artery disease // Eur Heart J. 2014 Sep 1;35(33):2260-1
2. Federal Guide to the Use of Medicines (formulary system) Issue XVIII. 2021.
3. Fihn SD, Gardin JM, Abrams J. et al. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association TaskForce on, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons // J Am Coll Cardiol. 2012. 60: e44–64.
4. State Register of Medicines https://grls.rosminzdrav.ru
5. Kawanishi DT, Reid CL, Rahimtoola SH Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a doubleblind randomized individualized dosing trial of nifedipine, propranolol and their combination // J Am Coll Cardiol. 1992. 19: 409-17.
6. Meyer TE, Adnams C., Commerford P. Comparison of the efficacy of atenolol and its combination with slow-release nifedipine in chronic stable angina // Cardiovasc DrugsTher. 1993. 7: 909-913.
7. Law MR, Morris JK, Wald NJ Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomized trials in the context of expectations from prospective epidemiological studies // BMJ. 2009; 338:b1665.
8. Shalnova S.A., Deev A.D., Oganov R.G. Factors influencing mortality from cardiovascular diseases in the Russian population // Cardiovascular therapy and prevention. 2006. 2: 73–77.
9. Bhatt DL, Steg PG, Ohman EM et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis // JAMA. 2006. 295: 180–189.
10. Mancia G, Fagard R, Narkiewicz K. et al. ESH/ESC Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) // J Hypertans. 2013. 31: 1281–1357.
11. Clinical recommendations “Diagnostics and treatment of hypertension” // Cardiological Bulletin. 2015. Volume X, No. 1:5-30
12. Chazova I.E., Ratova L.G., Boytsov S.A., Nebieridze D.V. Diagnosis and treatment of arterial hypertension // Systemic hypertension. 2010. 7 (3): 5–26.
13. Hjalmarson A., Herlitz J., Holmberg S., Rydén L., Swedberg K., Vedin A., Waagstein F., Waldenström A., Waldenström J., Wedel H., Wilhelmsen L., Wilhelmsson C.The Göteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction // Circulation. 1983. 67(6 Pt 2):I26-32.
14. Kirichenko A.A. Coronary heart disease and heart rate control // Consilium Medicum. 2015. 17 (5): 23–25.
15. Shpector A.V., Vasilyeva E.Yu. Modern approaches to secondary prevention of acute myocardial infarction // Creative Cardiology. 2014. 2: 71–80.
16. Gillman M., W. Kannel, A. Belanger Influence of heart rate on mortality among persons with hypertension: The Framingham study. // Am Heart J. 1993. Vol. 125: 1148-1154.
17. Gillum R., Makuc D., Feldman J. Pulse rate, coronary heart disease, and death: The NHANES I epidemiologic follow-up study // Am Heart J. 1991. 121: 172-177.
18. Oganov R.G., Konstantinov V.V., Kapustina A.V., Deev A.D., Shalnova S.A., Vikhireva O.V. and others. Pulse frequency and mortality from cardiovascular diseases in Russian men and women. Results of an epidemiological study // Cardiology. 2005. 45(10):45-50.
19. Bramah N. Singh Morbidity and Mortality in Cardiovascular Disorders: Impact of Reduced Heart Rate // J Cardiovasc Pharmacol Ther. 2001. 6(4): 313-331.
20. Gillum, R.D.Kuc, J.Feldman. Pulse rate, coronary heart disease, and death: The NHANES I epidemiologic follow-up study // Am Heart J. 1991. 121: 172-177.
21. Fomin I.V., Polyakov D.S., Badin Yu.V. Epoch: arterial hypertension and coronary heart disease as the main causes of CHF // Effective pharmacotherapy. 2011. 12:16-20.
22. 2012-ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease // Circulation. 2012. 126: 354-371.
23. Montalescot G., Sechtem U. et al. 2013 ESC guidelines on the management of stable coronary artery disease // Eur Heart J. 2013. 34(38):2949-3003.
24. Cordero A., Bertomeu-González V., Mazón P., Moreno-Arribas J., Fácila L., Bueno H., González-Juanatey JR, Bertomeu-Martínez V. Differential effect of β-blockers for heart rate control in coronary artery disease // Clin Cardiol. 2011. 34(12):748-754.
25. Kobalava Z., Khomitskaya Y., Kiyakbaev G.; ATHENA trial investigators. Achievement of target resting heart rate on beta-blockers in patients with stable angina and hypertension (ATHENA) in routine clinical practice in Russia // Curr Med Res Opin. 2014. 30(5):805-811.
26. Vitale C., Iellamo F., Volterrani M., Lombardi M., Fini M., Banach M., Rosano GM. Heart rate control in an unselected consecutive population of outpatients with stable coronary artery disease: Analysis of the CARDIf Study Cohort // Angiology. 2010. 61(8):763-767.
27. Standard of emergency medical care for tachycardias and tachyarrhythmias. Order of the Ministry of Health of the Russian Federation dated July 5, 2016 No. 464 n “On approval of the standard of emergency medical care for tachycardias and tachyarrhythmias.” https://www.garant.ru/products/ipo/prime/doc

Overdose

Manifested by dizziness, drop in blood pressure, sinus bradycardia , arrhythmias, fainting, ventricular extrasystole , cardiogenic shock, heart failure, cardiac arrest, bronchospasm , nausea, vomiting, coma, loss of consciousness.

The first symptoms are observed 20 minutes after taking increased doses of the drug.

The administration of enterosorbents and timely gastric lavage are required. If there is a significant drop in blood pressure, the patient is placed in a Trendelenburg position and norepinephrine, Dobutamine , and Dopamine . Later glucagon , and an intracardial pacemaker is installed in a transvenous manner as needed.

Diazepam is administered slowly intravenously . When bronchospasm develops, beta-2 adrenergic stimulants are administered intravenously.

Hemodialysis has not proven effective.

Interaction

Extracts of allergens used for skin testing, the allergens themselves significantly increase the likelihood of developing anaphylaxis, severe systemic allergic reactions in patients who use Metoprolol.

The risk of developing anaphylactic reactions increases with intravenous administration of radiocontrast drugs based on iodine . Medicines for general inhalation anesthesia, phenytoin when administered intravenously increase the likelihood of a drop in blood pressure and increase the severity of the cardiodepressive effect.

Metoprolol can mask the symptoms of hypoglycemia (high blood pressure, tachycardia ) and change the effectiveness of oral forms of hypoglycemic agents, insulin.

The drug reduces the clearance of xanthines, lidocaine , increasing their concentration in the blood plasma, especially in patients with increased clearance of theophylline with concomitant smoking.

Estrogens, glucocorticosteroids, NSAIDs weaken the hypotensive effect of the drug.

Methyldopa , Reserpine , BMCC, cardiac glycosides, antiarrhythmic drugs, Amiodarone , Diltiazem , Verapamil , guanfacine - aggravate the course of bradycardia , heart failure , atrioventricular block .

When taking Nifedipine, a significant drop in blood pressure is observed. Hydralazine , sympatholytics, clonidine , diuretics, and other antihypertensive drugs can provoke a sharp and excessive drop in blood pressure.

Metoprolol prolongs the period of anticoagulant action of coumarins and increases the period of action of non-depolarizing muscle relaxants. Antipsychotic drugs, tetracyclic antidepressants, neuroleptics, tricyclic antidepressants, hypnotics and sedatives, ethanol - enhance the inhibitory effect of metoprolol on the central nervous system.

The simultaneous administration of MAO inhibitors is unacceptable due to the risk of a sharp drop in blood pressure.

Impaired peripheral circulation is observed when non-hydrogenated ergot alkaloids are prescribed.

Metoprolol 50 mg

Metoprolol

Registration number: LP-000950

Trade name of the drug: Metoprolol

International nonproprietary name: metoprolol

Dosage form: tablets

Composition per tablet: metoprolol tartrate 0.05 g or 0.1 g (calculated as 100% substance).

Excipients: lactose monohydrate (milk sugar) - 0.08949 g or

0.12778 g, potato starch - 0.04275 g or 0.06349 g, povidone (kollidon 30 or plasdon K-29/30) - 0.003 g or 0.0048 g, colloidal silicon dioxide (Aerosil 300) - 0.003 g or

0.0048 g, crospovidone (kollidon CL-M or polyplasdon XL-10) – 0.007 g or 0.0112 g, magnesium stearate – 0.002 g or 0.0032 g, stearic acid – 0.002 g or 0.0032 g.

Description: round tablets of a flat-cylindrical shape with a chamfer and a score, white or white with a yellowish tint. Slight marbling is allowed.

Pharmacotherapeutic group: selective beta1-blocker

ATX code: [С07АВ02]

Pharmacological properties

Pharmacodynamics Cardioselective beta1-blocker. It has a slight membrane-stabilizing effect and does not have internal sympathomimetic activity. It has antihypertensive, antianginal and antiarrhythmic effects.

By blocking beta1-adrenergic receptors of the heart, it reduces the catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate, reduces the intracellular calcium current, has a negative chrono-, dromo-, batmo- and inotropic effect (reduces heart rate, inhibits conductivity and excitability, reduces myocardial contractility ).

The total peripheral vascular resistance at the beginning of the use of beta-adrenergic blockers (in the first 24 hours after oral administration) increases (as a result of a reciprocal increase in the activity of alpha-adrenergic receptors and the elimination of stimulation of beta2-adrenergic receptors), which returns to the original level after 1-3 days, and with long-term use it decreases.

The antihypertensive effect is due to a reflex decrease in minute blood volume and renin synthesis, inhibition of the activity of the renin-angiotensin-aldosterone system (of greater importance in patients with initial hypersecretion of renin) and the central nervous system, restoration of the sensitivity of the baroreceptors of the aortic arch (there is no increase in their activity in response to decrease in blood pressure) and ultimately a decrease in peripheral sympathetic influences. Reduces high blood pressure (BP) at rest, during physical exertion and stress. The antihypertensive effect develops quickly (systolic blood pressure decreases after 15 minutes, maximum after 2 hours) and lasts for 6 hours, diastolic blood pressure changes more slowly: a stable decrease is observed after several weeks of regular use.

The antianginal effect is determined by a decrease in myocardial oxygen demand as a result of a decrease in heart rate (prolongation of diastole and improvement of myocardial perfusion) and contractility, as well as a decrease in the sensitivity of the myocardium to the effects of sympathetic innervation. Reduces the number and severity of angina attacks and increases exercise tolerance. By increasing the end-diastolic pressure in the left ventricle of the heart and increasing the stretching of the muscle fibers of the ventricles, it can increase the myocardial oxygen demand, especially in patients with chronic heart failure. The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP content, arterial hypertension), a decrease in the rate of spontaneous excitation of sinus and ectopic pacemakers and a slowdown in atrioventricular (AV) conduction (mainly in the antegrade and to a lesser extent in the retrograde directions through the AV node) and along additional paths.

In case of supraventricular tachycardia, atrial fibrillation, sinus tachycardia in functional heart diseases and thyrotoxicosis, it reduces the heart rate (HR) or can even lead to rhythm restoration.

Prevents the development of migraine.

In contrast to non-selective beta-blockers, when used in average therapeutic doses, it has a less pronounced effect on organs containing beta2-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism. When used in large doses (more than 100 mg/day), it blocks beta1 and beta2 adrenergic receptors.

Pharmacokinetics Absorption in the gastrointestinal tract when taken orally is complete (95%). Solubility in fats is moderate. Subjected to intensive first-pass metabolism, bioavailability is 50% upon first administration and increases to 70% upon repeated use. Communication with blood plasma proteins - 10%. The time to reach the maximum concentration of metoprolol is 1.5-2 hours. During the course of treatment, bioavailability increases. Eating increases bioavailability by 20 - 40%.

It is quickly distributed in tissues, penetrates the blood-brain barrier, and the placental barrier. Penetrates into breast milk (concentration higher than in blood plasma).

Metabolized in the liver, two metabolites have beta-blocking activity. The CYP2D6 isoenzyme takes part in the metabolism of the drug. The half-life of metoprolol ranges from 3.5 to 7 hours when taken orally. It is not removed by hemodialysis.

A significant accumulation of metabolites is observed in patients with a creatinine clearance of 5 ml/min, while the beta-blocking activity of the drug does not increase.

Bioavailability increases in liver failure, while its overall clearance is reduced.

Indications for use

Arterial hypertension (in monotherapy or in combination with other antihypertensive drugs); functional disorders of cardiac activity accompanied by tachycardia; coronary heart disease: myocardial infarction (secondary prevention - complex therapy), prevention of angina attacks; heart rhythm disturbances (supraventricular tachycardia; ventricular extrasystole); hyperthyroidism (complex therapy); prevention of migraine attacks.

Contraindications

Hypersensitivity to metoprolol, other components of the drug and other beta-blockers, cardiogenic shock, grade II-III atrioventricular block, sinoatrial block, sick sinus syndrome, severe bradycardia (heart rate less than 50 beats/min), acute and chronic heart failure in stages of decompensation, Prinzmetal's angina, acute myocardial infarction (heart rate less than 45 beats/min, PQ interval more than 0.24 s, systolic blood pressure less than 100 mm Hg), pheochromocytoma (without simultaneous use of alpha-blockers), concomitant use of monoamine oxidase inhibitors or simultaneous intravenous administration of verapamil; lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome, severe peripheral circulatory disorders, severe forms of bronchial asthma and a history of bronchospasm; age up to 18 years, lactation period.

Directions for use and doses

Orally, during or immediately after a meal, the tablets can be divided in half (but not chewed) and washed down with liquid. For arterial hypertension (in monotherapy or in combination with other antihypertensive drugs), the initial dose is 50-100 mg 1-2 times a day (morning and evening); if the therapeutic effect is insufficient, the daily dose can be increased to 100-200 mg. The maximum daily dose is 200 mg.

For functional disorders of cardiac activity accompanied by tachycardia - 50 mg 2 times a day (morning and evening). Elderly patients are recommended to start treatment with 50 mg/day.

Coronary heart disease: myocardial infarction (secondary prevention) - 200 mg/day, divided into 2 doses (morning and evening).

Prevention of angina attacks, in case of heart rhythm disturbances - 100-200 mg 1-2 times a day (morning and evening).

For hyperthyroidism - 50 mg 2 times a day (morning and evening).

Prevention of migraine attacks - 100-200 mg 1-2 times a day (morning and evening).

Carefully

Diabetes mellitus, metabolic acidosis, bronchial asthma, chronic obstructive pulmonary disease, renal/liver failure, myasthenia gravis, pheochromocytoma (with simultaneous use with alpha-blockers), thyrotoxicosis, stage I atrioventricular block, depression (including in history) , psoriasis, peripheral circulatory disorders (“intermittent” claudication, Raynaud’s syndrome), aggravated allergic history, pregnancy, old age.

Overdose

Symptoms: severe sinus bradycardia, dizziness, atrioventricular block (up to the development of complete transverse block and cardiac arrest), marked decrease in blood pressure, fainting, arrhythmia, ventricular extrasystole, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, loss of consciousness, coma, nausea, vomiting, cyanosis, convulsions, hypoglycemia. The first signs of overdose appear 20 minutes - 2 hours after taking the drug. Treatment: gastric lavage and taking absorbent medications; symptomatic therapy: with a pronounced decrease in blood pressure, the patient should be in the Trendelenburg position; in case of excessive decrease in blood pressure, bradycardia and heart failure - intravenously (i.v.), with an interval of 2-5 minutes, beta-agonists - until the desired effect is achieved or i.v. 0.5-2 mg of atropine. If there is no positive effect, dopamine, dobutamine or norepinephrine. For hypoglycemia - administration of 1-10 mg of dextrose solution, installation of a transvenous intracardial pacemaker. For bronchospasm, beta2-adrenergic agonists are used. For convulsions - slow intravenous administration of diazepam. Hemodialysis is ineffective.

special instructions

Monitoring of patients taking beta-blockers includes monitoring heart rate and blood pressure (at the beginning of treatment - daily, then once every 3-4 months), blood glucose concentration in patients with diabetes (once every 4-5 months). The patient should be taught how to calculate heart rate and instructed about the need for medical consultation if the heart rate is less than 50 beats/min.

It is possible that the severity of allergic reactions may increase (against the background of a burdened allergic history) and there will be no effect from the administration of usual doses of epinephrine (adrenaline). In elderly patients, it is recommended to monitor kidney function (once every 4-5 months).

May increase symptoms of peripheral arterial circulation disorders. For exertional angina, the selected dose of the drug should ensure the heart rate at rest within the range of 55-60 beats/min, and during exercise - no more than 110 beats/min. In smokers, the effectiveness of beta-blockers is lower.

Metoprolol may mask some clinical manifestations of thyrotoxicosis (for example, tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, as it can intensify symptoms.

In diabetes mellitus, it can mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentrations to normal values.

If necessary, use in patients with concomitant bronchial asthma requires additional use of beta2-adrenergic agonists; for pheochromocytoma - alpha-blockers.

If surgical intervention is necessary, it is necessary to warn the surgeon/anesthesiologist about taking metoprolol (the choice of drugs for general anesthesia with minimal negative inotropic effect); discontinuation of the drug is not recommended. In the event of increasing bradycardia (less than 50 beats per minute), arterial hypotension (systolic blood pressure below 100 mm Hg), AV block, bronchospasm, ventricular arrhythmias, severe impairment of liver and kidney function, it is necessary to reduce the dose or discontinue treatment. It is recommended to discontinue therapy if skin rashes appear and depression develops caused by taking beta-blockers. The drug is discontinued gradually, reducing the dose over 10 days. If treatment is abruptly stopped, nightmare dream syndrome may occur; very rarely - amnesia/memory impairment, depression, hallucinations, slowing of the speed of mental and motor reactions, muscle cramps, asthenia, myasthenia gravis. . From the senses: rarely - blurred vision, dry and sore eyes, conjunctivitis, decreased secretion of tear fluid; very rarely - ringing in the ears, disturbance of taste. . From the digestive system: often - nausea, abdominal pain, constipation or diarrhea; infrequently - vomiting; rarely - dryness of the oral mucosa, impaired liver function, hepatitis.

From the skin: infrequently - urticaria, increased sweating; rarely - alopecia; very rarely - photosensitivity, exacerbation of psoriasis, skin itching, rash, skin hyperemia, psoriasis-like skin reactions. . From the respiratory system: often - shortness of breath with physical effort; uncommon – bronchospasm in patients with bronchial asthma; rarely – rhinitis.

Other: infrequently - weight gain; very rarely - arthralgia, thrombocytopenia; Peyronie's disease, hypoglycemia, hyperglycemia, increased titer of antinuclear antibodies, decreased libido, potency.

Interaction with other drugs

Barbiturates increase the metabolism of metoprolol due to the induction of microsomal liver enzymes.

Propafenone increases the plasma concentration of metoprolol by 2-5 times (probably due to inhibition of the CYP2D6 isoenzyme by propafenone). Simultaneous intravenous administration of verapamil can cause bradycardia and a marked decrease in blood pressure.

Class I antiarrhythmic drugs can lead to additive negative inotropic effects with the development of severe hemodynamic side effects in patients with impaired left ventricular function (this combination should be avoided in patients with sick sinus syndrome or impaired AV conduction).

Amiodarone is a risk of developing severe sinus bradycardia (including long after discontinuation of amiodarone, due to its long half-life).

Diltiazem is a risk of developing severe bradycardia (mutually enhancing the inhibitory effect on AV conduction and sinus node function). The antihypertensive effect is weakened by glucocorticosteroids and estrogens (sodium ion retention).

Beta-adrenergic agonists, aminophylline, theophylline, indomethacin and other non-steroidal anti-inflammatory drugs weaken the antihypertensive effect.

Diphenhydramine reduces the clearance of metoprolol, enhancing its effect. Epinephrine - the risk of developing a pronounced decrease in blood pressure and bradycardia. Phenylpropanolamine in high doses causes a paradoxical increase in blood pressure (up to a hypertensive crisis).

Quinidine inhibits the metabolism of metoprolol in rapid metabolizers, leading to a significant increase in plasma concentrations of metoprolol and an increase in its beta-blocking effect.

Clonidine - there is a risk of a pronounced increase in blood pressure when clonidine is abruptly discontinued while taking beta-blockers simultaneously, therefore, if clonidine is discontinued, gradual cessation of beta-blockers should be started several days before its discontinuation.

Rifampicin - enhances the metabolism of metoprolol, reducing plasma concentrations (due to the induction of microsomal liver enzymes). Cimetidine and hydralazine increase the concentration of metoprolol in the blood. Medicines for inhalation anesthesia (halogenated hydrocarbons) enhance the cardiodepressive effect of metoprolol. Incompatible with monoamine oxidase type A inhibitor.

Cardiac glycosides, methyldopa, reserpine, guanfacine and clonidine increase the risk of bradycardia.

Nifedipine, in addition to enhancing the antihypertensive effect, can lead to the development

heart failure.

Tri- and tetracyclic antidepressants, antipsychotic drugs (neuroleptics), ethanol, sedatives and hypnotics increase depression of the central nervous system.

With the simultaneous use of metoprolol and sympatholytics, nitroglycerin, barbiturates, vasodilators (alprostadil) and other antihypertensive drugs (for example, prazosin), the antihypertensive effect may be enhanced, therefore patients taking such combinations of drugs should be under constant medical supervision to detect an excessive decrease in blood pressure or bradycardia.

Changes the effectiveness of insulin and oral hypoglycemic agents. Increases the risk of developing hypoglycemia, enhances its severity and duration, masks its symptoms (tachycardia, sweating, increased blood pressure).

When used together with ethanol, the risk of a pronounced decrease in blood pressure increases and an increased inhibitory effect on the central nervous system is noted.

Reduces the clearance of lidocaine and increases its concentration in the blood plasma, especially in patients with initially increased clearance of theophylline under the influence of smoking.

Non-hydrogenated ergot alkaloids increase the risk of developing peripheral circulatory disorders.

Prolongs the effect of antidepolarizing muscle relaxants and the anticoagulant effect of coumarin derivatives.

Aldesleukin increases arterial hypotension.

Mefloquine increases inhibition of conduction and excitability of the heart muscle.

When used simultaneously with norepinephrine, epinephrine, other adrenergic and sympathomimetics (including in the form of eye drops or as part of antitussives), a slight increase in blood pressure is possible.

Allergens used for immunotherapy or allergen extracts for skin testing increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving metoprolol. Iodine-containing radiopaque drugs for intravenous administration increase the risk of anaphylactic reactions.

Use during pregnancy and breastfeeding

During pregnancy, it is prescribed only according to strict indications if the expected benefit to the mother outweighs the potential risk to the fetus (due to the possible development of bradycardia, arterial hypotension, hypoglycemia and respiratory depression in the newborn). Treatment must be interrupted 48-72 hours before delivery. In cases where this is not possible, it is necessary to ensure strict monitoring of newborns for 48 to 72 hours after delivery.

Since metoprolol passes into breast milk, the drug should not be taken during breastfeeding or the mother should stop breastfeeding during treatment.

Impact on the ability to drive vehicles and machinery

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Release form

Tablets of 50 mg and 100 mg.

10 or 20 tablets in a blister pack made of polyvinyl chloride film and aluminum foil.

30 tablets per jar made of polymer materials.

Each jar or 3 or 5 blister packs of 10 tablets or 2 blister packs of 20 tablets, together with instructions for use, are placed in a cardboard pack for consumer packaging.

Storage conditions:

In a dry place, protected from light, at a temperature not exceeding 25ºС.

Best before date:

2 years. Do not use after the expiration date.

Units:

pack

special instructions

Monitoring of patients using beta-blockers includes regular monitoring of blood pressure, pulse, and sugar levels. It is important to teach the patient to keep track of the pulse rate, and in case of bradycardia, he needs to seek the help of his attending physician.

Elderly people need to monitor the functioning of the renal system.

Metoprolol can cause peripheral arterial circulatory disorders.

Metoprolol is withdrawn gradually over at least 10 days.

Taking more than 200 mg per day leads to a decrease in cardioselectivity.

When taking the drug, it is possible to mask the clinical picture of thyrotoxicosis ( tachycardia ).

When planning a surgical intervention, it is necessary to notify the anesthesiologist about taking the drug Metoprolol, and do not stop taking the drug.

arterial hypotension , increasing bradycardia , ventricular arrhythmia , atrioventricular block, severe pathology of the liver and kidneys are registered in elderly people

Treatment is stopped if depression develops or skin rashes appear.

When taking the drug during pregnancy, it should be discontinued 48-72 hours before the expected birth.

Metoprolol has an effect on driving vehicles and performing complex work.

Recipe in Latin:

Rp: Metoprololi 0.05 D. td No. 100 in tab. S. 1 tablet. 2-3 times a day.

Metoprolol analogs

Level 4 ATC code matches:
Biol

Metocard

Metozok

Nebilet

Nebilong

Betaxolol

Bisogamma

Aritel

Cordinorm

Vasocardin

Corvitol

Bidop

Bisoprolol

Nebivolol

Biprol

Bisoprol

Concor Cor

Lokren

Concor

Niperten

Metoprolol-Acri, Metoprolol-Ratiopharm, Metoprolol-OBL, Metoprolol Organica, Metoprolol Zentiva are synonymous drugs.

The following analogues of Metoprolol are also distinguished:

• Egilok
• Betalok
• Metocard
• Metocore
• Serdol
• Anepro
• Vasocardin
• Corvitol
• Metobloc
• Metoprol
• Emzok

Metoprolol price, where to buy

The price of Metoprolol in tablets of 50 mg is on average 40 rubles per pack of 30 pieces.

• Online pharmacies in RussiaRussia
• Online pharmacies in UkraineUkraine

ZdravCity

• Metoprolol Retard-Akrikhin tablets p.p.o.
  prolonged action 100 mg 30 pcs. JSC Akrikhin 364 rub. order
• Metoprolol-Teva tablets 100 mg 30 pcs. Merkle GmbH

  51 RUR order

• Metoprolol-Teva tablets 50 mg 30 pcs. Merkle GmbH

  29 RUR order

• Metoprolol tab. 25mg No. 60Pranafarm LLC

  69 RUR order

• Metoprolol tablets 25 mg 60 pcs. Ozon LLC

  65 rub. order

Pharmacy Dialogue

• Metoprolol (25 mg tablet No. 60) Organics (Novokuznetsk Autonomous Okrug)

  63 RUR order

• Metoprolol (25 mg tablet No. 60) Ozon LLC

  59 RUR order

• Metoprolol retard-Akrikhin tablets 100 mg No. 30 Akrikhin OJSC

  RUB 301 order

• Metoprolol Welfarm (50 mg tablet No. 30) Welfarm LLC

  68 RUR order

• Metoprolol retard-Akrikhin extended-release tablets 50 mg No. 30 Akrikhin OJSC

  220 rub. order

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Pharmacy24

• Metoprolol tartrate 50 mg No. 20 tablets PAT "Farmak", Ukraine
  13 UAH. order
• Metoprolol-KMP 50 mg N30 tablets PAT "Kievmedpreparat", Ukraine

  11 UAH order

• Metoprolol tartrate 100 mg No. 20 tablets PAT "Farmak", Ukraine

  16 UAH order

• Metoprolol-KMP 100 mg N30 tablets PAT "Kievmedpreparat", Ukraine

  20 UAH order