Pharmacodynamics. Metoprolol is a cardioselective β1-adrenergic receptor blocker. does not have a membrane stabilizing effect and has no internal sympathomimetic activity.
It suppresses the effects of increased sympathetic activity in the heart, significantly reduces heart rate, cardiac contractile activity, cardiac output and blood pressure.
In hypertension, metoprolol lowers blood pressure in patients both in the standing position and in the supine position. The long-term antihypertensive effect of the preparation is associated with a gradual decrease in the systemic vascular resistance.
In patients with hypertension, prolonged use of the preparation leads to a statistically significant decrease in left ventricular mass and an improvement in left ventricular diastolic function.
In men with mild to moderate hypertension, metoprolol reduces mortality caused by cardiovascular diseases (primarily the incidence of sudden death, fatal myocardial infarctions and strokes).
Due to a decrease in systemic blood pressure, a decrease in heart rate and contractile activity of the heart, metoprolol reduces myocardial oxygen demand. By decreasing heart rate, and thus lengthening the duration of diastole, metoprolol improves perfusion and oxygenation of myocardial areas with impaired blood supply.
In addition, the preparation reduces the number, duration and severity of angina attacks, as well as asymptomatic ischemia, and increases exercise tolerance.
In myocardial infarction, metoprolol reduces mortality by reducing the risk of sudden death. This effect is primarily associated with the prevention of ventricular fibrillation. A decrease in mortality is noted regardless of whether metoprolol was used at an early or late stage of the disease, as well as in cases of increased risk and in patients with diabetes mellitus.
When using metoprolol after myocardial infarction, the risk of re-infarction is reduced.
With congestive heart failure due to dilated cardiomyopathy, metoprolol, initially prescribed at a low dose (2 times 5 mg / day), which was then gradually increased, improved heart function, quality of life and physical activity of patients; reduced readmissions for heart failure and the need for heart transplants.
With supraventricular tachycardia, atrial fibrillation and ventricular extrasystole, metoprolol reduces the ventricular frequency and the number of extraventricular contractions.
At therapeutic doses, the peripheral vasoconstrictor and bronchoconstrictor effect of metoprolol is less pronounced than that of non-selective β-adrenergic blockers.
Compared to nonselective β-adrenergic receptor blockers, metoprolol has a significantly lesser effect on insulin synthesis and carbohydrate metabolism. It only slightly alters the cardiovascular response to hypoglycemia or increases the duration of hypoglycemia.
In short-term clinical studies, metoprolol induced a slight increase in triglyceride levels and a slight decrease in plasma free fatty acid levels. In some cases, there was also a slight decrease in the level of HDL cholesterol, but it was less than with the use of non-selective β-adrenergic blockers. However, a long-term clinical study demonstrated a significant decrease in the level of total cholesterol in the blood plasma after several years of treatment with metoprolol.
Pharmacokinetics
Metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. The pharmacokinetic parameters of metoprolol are linear in the therapeutic dose range.
Cmax in blood plasma is reached 1.5–2 hours after administration. After absorption, metoprolol is metabolized during the first passage through the liver. Bioavailability of metoprolol is almost 50% after a single dose and almost 70% after repeated use.
Concomitant food intake can increase the bioavailability of metoprolol by 30-40%.
Plasma protein binding is low - about 5-10%.
Metoprolol is widely distributed in tissues and has a high volume of distribution (5.6 L / kg body weight).
Metoprolol is metabolized in the liver by cytochrome P450 enzymes. Metabolites have no pharmacological activity.
T½ - 3.5 hours on average (it varies within 1-9 hours).
The total ground clearance is approximately 1 L / min.
More than 95% of the dose taken is excreted in the urine, 5% is excreted unchanged. In some cases, the latter value can increase up to 30%.
In elderly patients, the pharmacokinetic parameters of metoprolol do not change significantly.
Renal failure does not affect the systemic bioavailability and elimination of metoprolol. However, in such cases, the excretion of metabolites is reduced. Significant accumulation of metabolites was observed in patients with renal insufficiency (glomerular filtration level - 5 ml / min). However, the accumulation of metabolites does not increase the degree of β-blockade.
Hepatic failure insignificantly affects the pharmacokinetic parameters of metoprolol. However, in severe liver cirrhosis and after portocaval anastomosis surgery, the bioavailability of metoprolol may increase, and the total clearance may decrease. In patients after portocaval anastomosis surgery, the total clearance decreased to approximately 0.3 L / min, and the AUC increased approximately 6 times compared with healthy individuals.
Ag, as monotherapy or in combination with other antihypertensive agents; to reduce mortality due to cardiovascular disease or coronary artery disease in patients with ag.
Angina pectoris. The preparation can be used as monotherapy or in combination with other antianginal agents.
In order to reduce mortality and the frequency of repeated myocardial infarction (as secondary prevention).
Violation of the heart rhythm (sinus tachycardia, supraventricular tachycardia, ventricular premature beats).
Functional disorders of cardiac activity, accompanied by tachycardia.
Prevention of migraine.
Egilok. tablets are taken with or without food. tablets can be split if necessary.
The dose should be set individually, gradually increasing to avoid excessive bradycardia.
Hypertension: for mild to moderate hypertension, the initial dose is 25 mg or 50 mg 2 times a day (morning and evening). If necessary, the daily dose can be gradually increased to 100 mg 2 times a day or other antihypertensive preparations can be used in combination with Egilok.
Angina pectoris: the initial dose of the preparation is 25 mg or 50 mg 2-3 times a day, which, if necessary, can be gradually increased to 200 mg / day, or the preparation can be combined with other antianginal agents.
Maintenance therapy after myocardial infarction: the usual dose is 50-100 mg 2 times a day (morning and evening).
Arrhythmia: the initial dose is 25-50 mg 2 or 3 times a day. If necessary, the daily dose can be gradually increased to 200 mg or other antiarrhythmic preparations can be used in combination with Egilok.
Functional disorders of cardiac activity, accompanied by tachycardia: the usual daily dose is 50 mg 2 times a day (morning and evening), which, if necessary, can be increased to 100 mg 2 times a day.
Prevention of migraine: the usual daily dose is 50 mg 2 times a day (morning and evening), which, if necessary, can be increased to 100 mg 2 times a day.
Special patient groups
Patients with renal insufficiency do not need dose adjustment.
There is no need to change the dose in patients with liver cirrhosis, since the binding of metoprolol to plasma proteins is low (5–10%). In severe hepatic impairment (for example, after bypass surgery), it may be necessary to reduce the dose of metoprolol.
Elderly patients do not need dose reduction.
Egilok Retard. For all indications, the preparation should be taken once a day.
It is recommended to take the daily dose in the morning with a little water, without chewing the tablet. The tablets can be taken with or without food.
If necessary, the film-coated tablet can be broken in half.
To avoid bradycardia, the dose must be selected individually.
AH: the average daily dose is 50 mg in 1 dose. If necessary, the dose can be increased to 100-200 mg in 1 dose. To enhance the hypotensive effect, Egilok Retard can be used with other antihypertensive preparations.
Angina pectoris: the dose of the preparation is 50 mg / day in 1 dose. If necessary, the dose can be increased to 100-200 mg in 1 dose. To enhance the clinical effect, Egilok Retard can be used with other antianginal preparations.
After myocardial infarction, the maintenance dose is 200 mg once a day.
Stable chronic heart failure: the recommended initial dose of the preparation during the first 2 weeks is 25 mg / day. After 2 weeks, the dose can be increased to 50 mg once a day and then every 2 weeks it can double to 100 mg, then to 200 mg. It is recommended to gradually increase the dose when taking metoprolol preparations with an immediate mechanism of action until a daily dose of 25 mg is reached. In severe cases of heart failure, it is recommended to use low doses or non-prolonged-release metoprolol tablets.
For arrhythmias, the initial dose of the preparation is 50-200 mg once a day.
With functional disorders of the heart, the usual dose of the preparation is 50-200 mg 1 time per day.
For the prevention of migraine attacks - 100-200 mg / day in 1 dose.
Hypersensitivity to metoprolol or any other component of the preparation or to other β-adrenergic receptor blockers, grade II and III av blockade, severe sinus bradycardia, sick sinus syndrome, cardiogenic shock, severe peripheral circulatory disorders, decompensated heart failure, acute infarction, if heart rate 45 / min, p – q interval - 240 ms, systolic blood pressure - 100 mm Hg. Art., patients requiring long-term and continuous treatment with inotropic β-agonists.
From the side of the central nervous system: very often - increased fatigue; often - dizziness, headache; infrequently - paresthesias, muscle spasms, depression, impaired attention, drowsiness, insomnia, nightmares; rarely - nervousness, stress, sexual dysfunction; very rarely - amnesia, memory impairment, confusion, hallucinations.
From the side of the cardiovascular system: often - bradycardia, postural hypotension (very rarely with loss of consciousness), cold extremities, tachycardia; infrequently - exacerbation of symptoms of heart failure, AV block of the 1st degree, edema, pain in the region of the heart; rarely - arrhythmias, conduction disturbances; very rarely - gangrene caused by a pre-existing disorder of the peripheral circulation.
From the gastrointestinal tract: often - nausea, abdominal pain, diarrhea, constipation; infrequently - vomiting; rarely - dry mouth, changes in liver function indicators; very rarely - hepatitis.
On the part of the skin: infrequently - rash (urticaria, psoriasis-like and dystrophic skin lesions), increased sweating; rarely - alopecia; very rarely - photosensitivity, progression of psoriasis.
From the respiratory system: often - shortness of breath during exertion; infrequently - bronchospasm (even in the absence of obstructive pulmonary disease); rarely - rhinitis.
Sensory system: rarely - visual impairment, xerophthalmia and / or eye irritation, conjunctivitis; very rarely - ringing in the ears, taste disturbance.
Metabolic disorders: infrequently - an increase in body weight.
From the side of the blood system: very rarely - thrombocytopenia.
From the side of the musculoskeletal system: very rarely - arthralgia.
Special instructions
Anaphylactic shock can be difficult in patients taking metoprolol.
Metoprolol may exacerbate existing bradycardia.
Metoprolol may aggravate the symptoms of peripheral circulatory disorders.
It is necessary to avoid abrupt discontinuation of the preparation. Egilok is canceled gradually by a stepwise dose reduction over 7-10 days.
Abrupt withdrawal of the preparation can aggravate the symptoms of angina pectoris and lead to the development of myocardial infarction. Patients with coronary artery disease need special attention during preparation withdrawal.
Heart failure should be compensated for before starting metoprolol, and the state of compensation should be maintained throughout the treatment period.
Despite the fact that cardioselective β-adrenergic blockers have less effect on respiratory function than non-selective β-adrenergic blockers, it is recommended not to prescribe them to patients with COPD if possible. If it is necessary to prescribe metoprolol to patients with asthma, it may be necessary to simultaneously administer β2-agonists (tablets or spray) or change the dose of previously used β2-agonists.
When prescribing the preparation to patients with diabetes mellitus, it is necessary to constantly monitor carbohydrate metabolism and, if necessary, adjust the dose of insulin and oral antidiabetic preparations.
In patients with pheochromocytoma, metoprolol must be combined with α-adrenergic receptor blockers.
The bioavailability of metoprolol may increase in liver cirrhosis.
In patients receiving β-adrenergic receptor blockers, epinephrine can increase blood pressure and cause (reflex) bradycardia; this reaction is less possible with the use of selective β-adrenergic blockers.
Before any surgery, the anesthesiologist should be warned that the patient is taking metoprolol.
Since Egilok must be canceled before surgery, it must be canceled no later than 48 hours before surgery, except in special cases, such as thyrotoxicosis or pheochromocytoma.
In some cases, the administration of β-adrenergic receptor blockers before surgery may be beneficial because they can reduce the arrhythmogenic effects and coronary circulation during surgical stress, which brings about an advantage of sympathetic tone. In the case of a β-adrenergic receptor blocker, an anesthetic with a weak negative inotropic effect should be chosen to reduce the risk of myocardial depression.
Very rarely, preexisting moderate abnormalities of atrioventricular conduction may increase, sometimes with the development of atrioventricular block.
This preparation should not be prescribed to patients with hereditary fructose intolerance, impaired absorption of glucose-galactose, as well as sucrase / isomaltase deficiency.
Use during pregnancy and lactation. Due to the lack of data from controlled clinical studies during pregnancy and lactation, Egilok can be used only in cases where the benefits of using the preparation for the mother justify the possible risk to the fetus / child.
If possible, the use of metoprolol is discontinued 48–72 hours before the expected period of labor. If the administration of the preparation is unavoidable, nursing infants should be monitored continuously for several days (48–72 hours) after birth, since the preparation can enter the fetal bloodstream and cause bradycardia, respiratory depression, decreased blood pressure and hypoglycemia.
Despite the ability of metoprolol to penetrate the placental barrier, there were no signs of its fetotoxicity. Despite the fact that with the introduction of metoprolol in therapeutic doses, only a small amount of the preparation penetrates into breast milk and does not have a significant β-blocking effect on infants, they must be constantly monitored (bradycardia is possible).
Children. There is no experience of using the preparation in children.
The ability to influence the reaction rate when driving or working with other mechanisms. Since dizziness and weakness may occur when taking Egilok, it is necessary to refrain from driving and working with complex mechanisms for the period of treatment.
The antihypertensive effect of the preparation egilok and other antihypertensive preparations, as a rule, is cumulative. in order to avoid hypotension, constant monitoring of patients who receive combinations of such funds is necessary. however, the summation of the effects of antihypertensive preparations can be used as needed to achieve effective blood pressure control.
The preparation cannot be combined with such preparations:
verapamil (IV injected) or other similar calcium channel blockers (risk of asystole);
MAO inhibitors.
Care must be taken when combining with:
Symptoms: arterial hypotension, sinus bradycardia, av blockade, heart failure, cardiogenic shock, asystole, nausea, vomiting, cyanosis, bronchospasm, hypoglycemia, loss of consciousness, coma, in some cases - hypoglycemia.
Treatment: gastric lavage, intake of activated charcoal, with severe hypotension - β-adrenergic receptor agonists (norepinephrine) or intravenous administration of atropine (with bradycardia). If there is no effect, dopamine, dobutamine, norepinephrine (norepinephrine) should be prescribed. Glucagon (1-10 mg) may be effective. In severe cases, implantation of an artificial pacemaker may be necessary. Bronchospasm is eliminated by the introduction of intravenous β2-adrenergic agonists (for example, terbutaline). Metoprolol is practically not excreted from the body by hemodialysis.
At a temperature of 30 ° C.
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