Pharmacodynamics. Metoprolol is a β-adrenergic receptor blocker without intrinsic sympathomimetic activity. specifically blocks the action of catecholamines at the level of adrenergic β1-receptors. reduces myocardial oxygen demand during exercise, has a positive effect in long-term treatment of angina pectoris (reducing the frequency of pain attacks). reduces systolic blood pressure, especially after exertion, and prevents the development of reflex orthostatic hypotension. a decrease in diastolic blood pressure occurs after several weeks of regular use - metoprolol reduces the plasma activity of renin. inhibiting β2-adrenergic receptors, metoprolol can cause an increase in smooth muscle tone.
Pharmacokinetics. Absorption and distribution. After oral administration, metoprolol is completely absorbed. The concentration of metoprolol in blood plasma is linearly dependent on the dose taken within the therapeutic dose. Cmax in blood plasma is reached 1.5–2 hours after application (Tmax). Although plasma concentration varies from person to person, individual reproducibility is good. As a result of an important effect during the primary passage through the liver, the systemic bioavailability of metoprolol after administration of a single oral dose reaches 50%. After repeated use, it rises to 70%. Taking with meals can increase bioavailability by 30-40%. The rate of binding of metoprolol to blood plasma proteins is low (approximately 5-10%).
Biotransformation. Metoprolol undergoes almost complete oxidative metabolism in the liver by cytochrome P450 enzymes (mainly CYP 2D6 isoenzyme). Significant ethnic differences were noted regarding the distribution of persons with slow metabolism. The number of persons with a slow metabolism is 7% in Caucasians, but less than 1% in Mongoloids. In patients with a slow metabolism through the CYP 2D6 system, the concentration of metoprolol in the blood plasma can be several times higher than the concentration of the preparation in persons with a normal metabolic rate through the CYP 2D6 system. Nevertheless, the metabolism of metoprolol via the CYP 2D6-dependent pathway may not, or to a lesser extent, affect the safety and tolerability of metoprolol. In cirrhosis of the liver, an increase in the level of unmetabolized metoprolol in the blood plasma should be expected due to a decrease in the metabolic rate.
Metabolism and excretion from the body. Metoprolol is metabolized in the liver, with three metabolites being formed. Two of the three metabolites have weak β-blocking properties, but are not clinically significant.
Usually, more than 95% of an orally taken dose of the preparation is excreted in the urine. Approximately 5% of this dose is excreted unchanged in the urine; in some cases, the amount of the preparation that is excreted in the urine unchanged can reach 30%. T1 / 2 is 3.5 hours (1-9 hours). The total rate of elimination from blood plasma (clearance) reaches approximately 1000 ml / min.
In elderly patients, there were no significant changes in the pharmacokinetics of metoprolol compared with young patients.
Systemic bioavailability and excretion of metoprolol are not altered in patients with renal insufficiency. But the excretion of metabolites in such patients is reduced. In patients with a glomerular filtration rate of 5 ml / min, there is a significant accumulation of metabolites. This accumulation of metabolites does not have a β-blocking effect.
In patients with impaired liver function, the pharmacokinetics of metoprolol (due to the low level of protein binding) changes slightly. However, in patients with liver cirrhosis, the bioavailability of metoprolol may increase and the total clearance may decrease.
Ag. angina pectoris (including postinfarction). arrhythmia (including supraventricular tachycardia). emergency treatment of myocardial infarction and prevention of re-infarction. hyperkinetic cardiac syndrome. prevention of migraine attacks.
Metoprolol is intended to be taken daily, preferably in the morning. the tablet should be swallowed without chewing, with plenty of drinking water. the tablet can be divided into equal parts. To do this, take the tablet with the thumb and forefinger of both hands with the notch for dividing up, press with your thumbs and break the tablet into two halves along the break. during the dose selection period, heart rate should be monitored to prevent bradycardia. the maximum daily dose is 200 mg. if, after prolonged use of the preparation, discontinuation of treatment is required, then this should be done gradually and slowly, because a sudden withdrawal of the preparation can lead to a sharp increase in blood pressure, cardiac ischemia with exacerbation of angina pectoris or myocardial infarction.
AG. The recommended dose is 50-100 mg (once in the morning or divided into two doses - morning and evening). If the therapeutic effect is not achieved at such a dosage, the daily dose can be increased to 200 mg (divided into two doses - in the morning and in the evening), or the preparation should be combined with other antihypertensive preparations.
Angina pectoris (including after myocardial infarction). The recommended dose is 50-100 mg / day (1 time per day in the morning or 2 times in the morning and evening). If this dose does not give the desired therapeutic effect, it can be increased to 200 mg, divided into 2 doses (morning and evening). In this case, blood pressure should be checked. If necessary, the preparation can be combined with other preparations for the treatment of angina pectoris.
Arrhythmia (including supraventricular tachycardia). The recommended dose is 100-200 mg / day (a dose of 100 mg is taken once in the morning, a dose of 200 mg - 100 mg in the morning and 100 mg in the evening).
Treatment of the acute phase of myocardial infarction and prevention of re-infarction
Treatment of the acute phase. In acute myocardial infarction, treatment begins as soon as possible after hospitalization, constantly monitoring the work of the heart using an ECG and measuring blood pressure. The initial dose is 5 mg IV metoprolol tartrate. Depending on tolerability, the following doses of 5 mg of metoprolol tartrate can be administered intravenously at intervals of 2 minutes until a total maximum dose of 15 mg of metoprolol tartrate is reached. If the full dose of 15 mg, administered intravenously, is well tolerated, 15 minutes after the last intravenous administration, 50 mg is administered orally once. In the next 48 hours, 50 mg of metoprolol is taken orally every 6 hours. For patients who cannot tolerate a dose of 15 mg of metoprolol tartrate when administered intravenously, further therapy with oral administration should be started with caution with 25 mg.
Maintenance dose. The recommended dose is 200 mg in 2 divided doses (morning and evening). With a decrease in heart rate and / or blood pressure or other complications that require treatment, the preparation should be discontinued immediately.
Hyperkinetic heart syndrome. The recommended dose is 50-100 mg / day (apply once in the morning or divided into 2 doses - in the morning and in the evening). If this dose does not give the desired therapeutic effect, it can be increased to 200 mg, divided into 2 doses (morning and evening). In this case, you should check the level of blood pressure. The dose should be reduced when a therapeutic effect is achieved.
Prevention of migraine attacks. The recommended daily dose is 100-200 mg / day (a dose of 100 mg is taken 1 time in the morning, a dose of 200 mg - 100 mg in the morning and 100 mg in the evening).
Patients with impaired renal function. No dose adjustment required.
Patients with impaired liver function. Dose adjustment (dose reduction of metoprolol) is usually necessary for patients with impaired liver function (for example, with cirrhosis of the liver).
Elderly patients. No dose adjustment required.
Hypersensitivity to the components of the preparation or other blockers of β-adrenergic receptors; av block (ii and iii degrees), sinoatrial block; sick sinus syndrome; decompensated heart failure (pulmonary edema, hypoperfusion syndrome or arterial hypotension); severe bradycardia (heart rate ≤50 beats / min); shock; severe peripheral circulatory disorders with pain or trophic changes; arterial hypotension (systolic blood pressure 100 mm Hg); bronchial hyperactivity (eg BA), a severe form of chronic obstructive bronchopulmonary disease; acidosis; untreated pheochromocytoma; long-term or intermittent inotropic therapy with β-receptor agonists; the use of metoprolol is contraindicated in patients in whom intravenous administration of calcium antagonists such as verapamil and diltiazem or other antiarrhythmic preparations (disopyramide) is carried out; concomitant therapy with MAO-a inhibitors.
Metoprolol should not be prescribed to patients with suspected acute myocardial infarction with a heart rate of 50 beats / min, a P – Q interval of 0.24 s, or a systolic blood pressure of 100 mm Hg. Art.
The incidence of adverse reactions is determined as follows: very often (1/10); often: (1/100, 1/10); infrequently (1/1000, 1/100); rarely (1/10 000, 1/1000); very rare (1/10 000); the frequency is unknown (cannot be estimated from the available data).
From the side of the blood and lymphatic system: very rarely - thrombocytopenia, leukopenia.
From the immune system: very rarely - allergic rhinitis.
Metabolic and alimentary disorders: rarely - diabetes mellitus, exacerbation of diabetes mellitus; unknown - hypoglycemia (after prolonged, strict fasting or heavy physical exertion, hypoglycemic conditions may occur during preparation therapy).
From the side of the psyche: infrequently - sleep disturbances, nightmares, depression, hallucinations; very rarely - memory problems, personality changes, mood swings.
From the nervous system: infrequently - dizziness, headache, confusion, unusual dreaming, paresthesia; very rarely - a violation of taste.
From the side of the organ of vision: rarely - dryness in the eye or inflammation of the conjunctiva; very rarely - visual impairment.
On the part of the organ of hearing and balance: very rarely - a feeling of noise / ringing in the ears, hearing impairment.
From the side of the heart: rarely - tachycardia, bradycardia, conduction disturbances, exacerbation of heart failure; rarely - peripheral edema; very rarely - increased angina pectoris.
From the side of the vessels: infrequently - cold extremities; rarely - arterial hypotension, syncope; unknown - exacerbation of Raynaud's syndrome (this also applies to other forms of limb perfusion disorders).
On the part of the respiratory system, organs of the thoracic cavity and mediastinum: rarely - shortness of breath during exertion; unknown - respiratory distress syndrome (due to an increase in airway resistance, respiratory distress is possible in patients prone to bronchospastic reactions, especially in obstructive airway diseases).
From the digestive tract: infrequently - nausea, vomiting, abdominal pain, diarrhea, constipation; rarely - dry mouth.
From the hepatobiliary system: very rarely - hepatitis.
On the part of the skin and subcutaneous tissue: infrequently - hypersensitivity reactions, increased sweating; very rarely - psoriasis, increased severity of psoriasis, psoriasis-like rash, hair loss; unknown - violation of fat metabolism.
On the part of the musculoskeletal system and connective tissue: rarely - muscle spasms, muscle weakness; very rarely - arthritis.
From the reproductive system and mammary glands: very rarely - impotence / sexual dysfunction, Peyronie's disease.
From the side of the kidneys and urinary tract: very rarely - exacerbation of renal failure.
General disorders and reactions at the injection site: unknown - increased fatigue.
Laboratory indicators: very rarely - an increase in body weight, deviations from the norm on the part of liver function indicators; unknown - a decrease in the level of HDL cholesterol and an increase in the level of triglycerides with a normal level of total cholesterol.
When taking metoprolol tartrate, as with other β-adrenergic receptor blockers, it is necessary to control heart rate and heart rate (first daily, then once a month).
As a rule, when treating BA patients, β2-agonists (in tablets or aerosol) should be prescribed as concomitant therapy. In cases where these patients begin to take the preparation, an increase in the dose of β2-agonists may be required. The risk of exposure to the preparation on β2-receptors is lower than in the case of the use of conventional non-selective β1-adrenergic blockers in tablets.
Particularly careful medical supervision is necessary in the treatment of patients with diabetes mellitus (control of blood glucose levels), patients with unstable blood glucose levels, following a strict fasting diet, patients adhering to a long-term strict fasting and with great physical exertion - due to the possibility of developing severe hypoglycemic conditions.
Metroprolol can mask some of the clinical manifestations of thyrotoxicosis (eg tachycardia). Abrupt withdrawal of the preparation for patients with thyrotoxicosis is contraindicated due to a possible increase in the severity of symptoms.
Patients undergoing treatment for heart failure should receive therapy for this disease before starting metoprolol use, as well as during this treatment. Very rarely, pre-existing mild forms of AV conduction disorders can aggravate and lead to more severe AV block. Patients with grade I AV block should be treated very carefully with this preparation. Use metoprolol with caution in patients with myasthenia gravis. If bradycardia develops (heart rate 50–55 beats / min) during treatment with metoprolol, the dose should be reduced and / or the preparation should be gradually withdrawn. Due to its hypotensive effect, the preparation can increase the manifestations of symptoms of peripheral circulatory disorders, such as intermittent claudication.
If the preparation is used in patients with pheochromocytoma, an α-sympatholytic preparation should be taken in parallel.
If it is impossible to stop using Corvitol before the procedure under general anesthesia or before using a peripheral muscle relaxant, the anesthesiologist should be informed about the patient's use of Corvitol. It is not recommended to discontinue treatment during surgery. If the preparation intake must be canceled, the cancellation should be carried out no later than 48 hours before the operation, except in special cases, such as thyrotoxicosis or pheochromocytoma.
If it is necessary to discontinue treatment and, if possible, it should be discontinued within 10-14 days with a daily dose reduction of 25 mg / day for the last 6 days. During this period, special attention should be paid to patients with coronary artery disease. The risk of heart attacks, including sudden death, may increase with discontinuation of treatment with β-adrenergic receptor blockers. Therapy should not be abruptly canceled due to the possibility of withdrawal syndrome (increased angina attacks, increased blood pressure).
Metoprolol can cause a slight increase in TG levels and a decrease in the content of free fatty acids in the blood. In some cases, there was a slight decrease in the level of HDL, and it was significantly less compared with the intake of non-selective β2-adrenergic blockers. Nevertheless, one long-term study showed a significant decrease in the level of total cholesterol after treatment with metoprolol for several years.
Data on the efficacy and safety of the preparation in patients with severe stable heart failure (NYHA grade IV) are limited. These patients should be treated by physicians with specialized skills and experience.
In patients with Prinzmetal angina, the frequency and severity of angina attacks may increase as a result of α-receptor-mediated coronary vasoconstriction. Therefore, such patients should not be prescribed non-selective β-adrenergic blockers, selective β1-adrenergic blockers should be used with caution.
Anaphylactic shock is severe in patients receiving treatment with β-adrenergic receptor blockers.
Patients with a history of severe allergic reactions should be treated with metoprolol very carefully. Particular attention should also be paid to patients with allergic reactions who are treated with vaccines (desensitizing therapy). The usual doses of epinephrine may not be effective.
Patients using contact lenses should be aware that the preparation can reduce the secretion of tear fluid.
In some cases, β-receptor blockers can provoke the onset of psoriasis, an increase in the symptoms of this disease, or the appearance of exanthema resembling psoriasis. Β-receptor blockers should be prescribed to patients with a history of psoriasis only after careful benefit / risk assessment.
Patients with a history of depressive illness should be treated with metoprolol only after a careful assessment of the benefit-to-risk ratio.
Patients with severe renal impairment, with serious acute conditions and patients receiving combined treatment with digitalis preparations should be given special attention.
The preparation contains lactose, so it should not be administered to patients with hereditary lactase deficiency, galactose intolerance or impaired glucose / galactose metabolism.
Patients with acute myocardial infarction or unstable angina pectoris in the previous 28 days, as well as patients with impaired liver function (see APPLICATION), over the age of 80 years or under 40 years of age; patients with hemodynamically severe valve diseases, hypertrophic obstructive cardiomyopathy, patients during or within 4 months after cardiac surgery should be treated only under the supervision of a physician with specialized skills and experience.
Use during pregnancy and lactation. Metoprolol, like other medicines, should not be used during pregnancy and lactation unless absolutely necessary. Like other β-adrenergic receptor blockers, metoprolol can cause side effects such as bradycardia, hypotension and hypoglycemia in the fetus and newborn or in the breastfeeding infant.
As a rule, β-adrenergic receptor blockers suppress placental blood flow, which can cause premature birth, growth retardation and fetal death. Metoprolol can cause the development of bradycardia, arterial hypotension, hypoglycemia and respiratory depression in newborns, so it should be discontinued 48–72 hours before the expected onset of labor. If this is not possible, the infant should be closely monitored for 48–72 hours after birth.
On the other hand, the amount of metoprolol that an infant receives in breast milk to realize the potential effect of blocking β-adrenergic receptors is insignificant, provided that the doses of metoprolol that the mother receives are within the normal therapeutic range (with the exception of slow metabolizers). It is necessary to carefully monitor the condition of breastfed infants to identify the potential effects of blockade of β-adrenergic receptors.
In order for the concentration of the active ingredient in breast milk to be low, the child should not be fed for 3-4 hours after taking the preparation.
Reproduction studies in rats using metoprolol tartrate at doses 55.5 times the maximum recommended human dose have shown no evidence of impaired fertility, but rarely metoprolol can cause Peyronie's disease in men.
Children. The use of the preparation is contraindicated in children.
The ability to influence the reaction rate when driving or working with other mechanisms. The use of the preparation can affect activities requiring a high speed of mental and physical reactions, making quick decisions (for example, driving vehicles, servicing machines and mechanisms, working at height), therefore, during the period of treatment, one should refrain from driving vehicles, servicing machines and mechanisms, work at height. The likelihood of such an effect increases at the beginning of treatment, when the dose is increased or the preparation is changed, and when alcohol is consumed.
Patients should be closely monitored if they take ganglion blockers, other β-adrenergic receptor blockers (for example, eye drops) simultaneously with the preparation Corvitol.
Caution is recommended in the case of the combined use of certain antiarrhythmic preparations such as quinidine or amiodarone and propafenone, since β-adrenergic receptor blockers can enhance negative inotropic and negative dromotropic effects. Simultaneous administration with propafenone should be avoided. Propafenone inhibits the metabolism of metoprolol through cytochrome P450 2D6. The result of this combination is unpredictable, since propafenone also exhibits β-adrenergic receptor blocker properties.
The cardiodepressant effect of Corvitol and antiarrhythmic preparations (amiodarone, propafenone and other antiarrhythmic preparations) can be summed up. The effect of amiodarone (significant sinus bradycardia) may persist for a long time after the preparation is discontinued.
With the simultaneous use of the preparation Corvitol and cardiac glycosides, reserpine, α-methyldopa, guanfacine or clonidine, a significant decrease in heart rate or a slowdown in conduction may occur.
With the sudden cancellation of clonidine during treatment with β-adrenergic receptor blockers, blood pressure may increase. If it is necessary to cancel concomitant therapy with clonidine, the β-adrenergic receptor blocker should be discontinued several days before the withdrawal of clonidine.
In patients who concurrently with Corvitol take calcium antagonists of the verapamil type or diltiazem and / or preparations for the treatment of arrhythmias (such as disopyramide), negative inotropic and chronotropic effects are possible. Therefore, careful monitoring of the condition of such patients is recommended.
In patients receiving treatment with β-adrenergic receptor blockers, inhalation anesthetics enhance the cardiodepressant effect. Metabolic inducers or inhibitors can affect the plasma concentration of metoprolol. Plasma concentration of metoprolol decreases with rifampicin or may increase with cimetidine, phenytoin, alcohol, hydralazine and serotonin reuptake inhibitors (paroxetine, fluoxetine and sertraline).
The simultaneous use of metoprolol with lidocaine can delay the elimination of lidocaine from the body.
Iodine-containing X-ray contrast agents for intravenous administration increase the risk of anaphylactic reactions.
The simultaneous use of metoprolol and neuromuscular relaxants (eg, suxamethonium, tubocurarine) may increase neuromuscular blockade.
The simultaneous use of the preparation Corvitol with NSAIDs, such as indomethacin, can reduce the antihypertensive effect of metoprolol.
Cardioselective β-adrenoreceptor blockers have a significantly lesser effect on blood pressure when adrenaline is administered to patients than non-selective β-adrenergic blockers.
Since β-adrenergic receptor blockers can affect peripheral circulation, caution should be exercised when using preparations with a similar effect, such as ergotamine, at the same time.
Β-adrenergic receptor blockers can provoke paradoxical hypertensive reactions in patients using high doses of phenylpropanolamine.
With the simultaneous administration of β-adrenergic receptor blockers with insulin or oral antidiabetic agents, their effect may be enhanced or prolonged. In this case, the symptoms of hypoglycemia (especially tachycardia and tremor) can be masked or disappear. In such cases, it is necessary to carry out regular monitoring of blood glucose levels with a possible dose adjustment of hypoglycemic agents, if necessary.
Simultaneous administration with barbiturates should be avoided, since barbiturates (tested on pentobarbital) stimulate the metabolism of metoprolol by enzyme induction. Metoprolol is almost completely metabolized in the liver by enzymes of the cytochrome P450 system (mainly CYP 2D6 isoenzyme). Plasma concentrations of metoprolol may be affected by preparations that inhibit CYP 2D6, such as quinidine, terbinafine, paroxetine, fluoxetine, bupropion, thioridazine, ritonavir, hydroxychloroquine, kinine, sertraline, celecoxib, propafenone, and diphenhydramine. At the beginning of treatment with these preparations, it may be necessary to reduce the dose of metoprolol.
The simultaneous use of digitalis glycosides and β-adrenergic receptor blockers can increase the AV conduction time and cause bradycardia. Diphenhydramine reduces (2.5 times) the clearance of metoprolol to α-hydroxymetoprolol through the CYP 2D6 system in persons with rapid hydroxylation. The effects of metoprolol are enhanced. It is possible that diphenhydramine can inhibit the metabolism of other CYP 2D6 substrates.
Rifampicin can stimulate the metabolism of metoprolol through CYP 2D6, which leads to a decrease in its levels in blood plasma.
Caution should be exercised when combined with nitrates, tricyclic antidepressants, phenothiazines, diuretics and other vasodilators due to the risk of arterial hypotension and / or bradycardia.
Concomitant therapy with dihydropyridine calcium channel blockers (eg nifedipine) with metoprolol, like other β-adrenergic receptor blockers, increases the risk of arterial hypotension and heart failure in patients with latent heart failure.
Metoprolol counteracts the β1-effects of sympathomimetic agents, but has little effect on the bronchodilatory effect of β2-agonists when used at therapeutic doses.
With the simultaneous use of the preparation Corvitol and norepinephrine, epinephrine or other sympathomimetic substances (for example, those contained in cough suppressants, drops for the nose and eyes), a significant increase in blood pressure is possible.
With metoprolol therapy, a decrease in the response to epinephrine can be observed at doses that are usually used to treat allergic reactions.
Due to the possibility of developing severe hypertension, MAO inhibitors should not be used with the preparation.
Symptoms: depending on the degree of intoxication, the clinical picture is characterized mainly by symptoms from the cardiovascular and central nervous system. an overdose of metoprolol can lead to a marked decrease in blood pressure, sinus bradycardia, av-blockade of the i-iii degree, lengthening of the q-t interval, asystole, insufficient peripheral perfusion, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, depression or respiratory arrest, increased fatigue , impairment or loss of consciousness, tremor, seizures, increased sweating, paresthesia, coma, nausea, vomiting, esophageal spasms, hypoglycemia (especially in children), hyperglycemia, cyanosis, kidney damage and temporary myasthenic syndrome.
Concomitant use of alcohol, antihypertensive preparations, quinidine, or barbiturates may worsen the patient's condition. The first signs of an overdose may occur 20 minutes to 2 hours after an overdose.
Treatment is carried out in an intensive care unit with monitoring of vital functions. Reception of activated carbon, if necessary - gastric lavage. In the case of severe forms of arterial hypotension, bradycardia or the threat of heart failure, β1-agonist IV (for example, prenalterol) should be administered at intervals of 2-5 minutes, or by infusion until a therapeutic effect is achieved. In the absence of a selective β1 agonist, IV dopamine or atropine sulfate can be administered to block the vagus nerve. Atropine (0.25–0.5 mg for adults, 10–20 mcg / kg for children) should be given prior to gastric lavage because of the risk of vagal stimulation. Intubation and use of a respirator may be required; adequate restoration of the BCC; glucose infusion; ECG monitoring; repeated intravenous administration of atropine 1–2 mg (mainly for vagal symptoms). If a therapeutic effect is not achieved, other sympathomimetics such as dobutamine, isoprenaline, orciprenaline, epinephrine, or norepinephrine can be used.
You should also administer glucagon at a dose of 1–10 mcg / kg body weight IV, subsequently 2–2.5 mg / h can be administered as a continuous infusion. With significant bradycardia that does not respond to preparation therapy, an artificial heart rate driver should be used. For relief of bronchospasm, inhalation or intravenous β2-agonist or aminophylline intravenously should be administered. It should be borne in mind that the doses of antidotes required to eliminate the symptoms of an overdose of β-adrenergic receptor blockers are much higher than therapeutic ones, since β-receptors are linked by β-adrenergic receptor blockers.
In the case of generalized seizures, slow administration of diazepam is recommended.
At a temperature not higher than 25 ° C.
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