Metoprolol

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of a metoprolol of tartrate in 1 tablet.

Excipients: lactoses monohydrate, potato starch, povidone (polyvinylpirrolidone middlemolecular medical 3500±5000), magnesium stearate, sodium carboxymethylstarch (примогель), talc, silicon dioxide colloid (aerosil).

Pharmacological properties:

Pharmacodynamics. Metoprolol treats the cardioselective blockers of beta adrenoceptors which do not have internal sympathomimetic activity and membrane stabilizing properties. Possesses hypotensive, anti-anginal and antiarrhytmic action.

Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of tsAMF (cycloadenosinemonophosphate) from ATP (adenosinetriphosphate), reduces intracellular current of Sa2+, renders negative hrono-, dromo-, batmo-and inotropic action (urezhat heart rate, conductivity and excitability oppresses, reduces contractility of a myocardium).

The general peripheric resistance of vessels at the beginning of use of beta adrenoblockers (in the first 24 h after oral administration) increases (as a result of reciprocal increase of activity of alpha adrenoceptors and elimination of stimulation of beta2-adrenoceptors) which in 1-3 days is returned to initial, and at long appointment decreases.

Hypotensive action is caused by reduction of minute volume of blood circulation and synthesis of a renin, activity oppression system renin-angiotensin-aldosteronovoy (has bigger value at patients with initial hypersecretion of a renin) and the central nervous system, recovery of sensitivity of baroreceptors of an aortic arch (there is no strengthening of their activity in response to a lowering of arterial pressure) and as a result reduction of peripheral sympathetic influences. Reduces the increased arterial pressure at rest, at a physical tension and a stress. The hypotensive effect develops quickly (systolic arterial pressure decreases in 15 min., as much as possible - in 2 h) and proceeds during 6 h, diastolic arterial pressure changes more slowly: stable decrease is observed after several weeks of regular reception.

The anti-anginal effect is defined by decrease in need of a myocardium for oxygen as a result of reduction of heart rate (lengthening of a diastole and improvement of perfusion of a myocardium) and contractility, and also decrease in sensitivity of a myocardium to influence of a sympathetic innervation. Reduces number and weight of attacks of stenocardia and increases portability of an exercise stress. Due to increase in end diastolic pressure in a left ventricle and increases in stretching of muscle fibers of ventricles can increase oxygen requirement, especially at patients with chronic heart failure.

The antiarrhytmic effect is caused by elimination of aritmogenny factors (tachycardia, a superactivity of a sympathetic nervous system, the increased maintenance of tsAMF, arterial hypertension), reduction of speed of spontaneous excitement of sinus and ectopic pacemakers and delay of atrioventricular carrying out (it is preferential in antegrade and, to a lesser extent, in retrograde the directions through an atrioventricular node) and on additional ways.

At supraventricular tachycardia, atrial fibrillation, sinus tachycardia at functional heart diseases and a thyrotoxicosis urezhat heart rate or can even lead to recovery of a sinus rhythm.

Prevents development of migraine.

Unlike non-selective beta adrenoblockers at appointment in average therapeutic doses exerts less expressed impact on the bodies containing beta2-adrenoceptors (a pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchial tubes and a uterus) and on carbohydrate metabolism; expressiveness of atherogenous action does not differ from effect of propranolol. At long-term reception reduces concentration of cholesterol in blood. At use in high doses (more than 100 mg/days) renders the blocking effect on both subtypes of beta adrenoceptors.

Pharmacokinetics. Metoprolol quickly and almost is completely soaked up (95%) in digestive tract. Solubility in fats moderate. Is exposed to intensive presistemny metabolism, bioavailability — 50% at the first reception and increases up to 70% at repeated use. Communication with proteins of plasma — 10%. TCmax is 1,5-2 h after reception. During course treatment bioavailability increases. Meal increases bioavailability for 20-40%. It is quickly distributed in fabrics, gets through a blood-brain barrier, a placental barrier. Gets into maternal milk (concentration higher, than in plasma).

It is metabolized in a liver, 2 metabolites have beta and adrenoceptor blocking activity. CYP2D6 isoenzyme takes part in metabolism of drug. T1/2 is from 3,5 to 7 h at intake. About 5% of drug are removed in an invariable look by kidneys. Is not removed at a hemodialysis.

Considerable accumulation of metabolites is observed at patients with a creatine kinase of 5 ml/min., at the same time beta and adrenoceptor blocking activity of drug does not increase. Treatment of patients with reduced function of kidneys does not demand drug dose adjustment.

The abnormal liver function slows down drug metabolism, and in cases of insufficiency of function of a liver, the dose of drug has to be lowered.

Indications to use:

- arterial hypertension (as monotherapy or in a combination with other anti-hypertensive means), including hyperkinetic type, tachycardia;
- coronary heart disease: a myocardial infarction (secondary prevention — complex therapy), prevention of attacks of stenocardia;
- disturbances of a heart rhythm (supraventricular tachycardia and ventricular premature ventricular contraction);
- hyperthyroidism (complex therapy);
- prevention of attacks of migraine.

Route of administration and doses:

Inside, in time or right after meal, tablets can be halved, but not to chew and wash down with liquid.

At arterial hypertension an initial dose — 50-100 mg in 1-2 receptions (in the morning and in the evening), at insufficient therapeutic effect the daily dose can be raised to 100-200 mg or in addition apply other anti-hypertensive means. Maximum daily dose of 200 mg.

Secondary prevention of a myocardial infarction — 200 mg a day in two steps (in the morning and in the evening).

At stenocardia, arrhythmia, prevention of attacks of migraine — 100-200 mg a day in two steps (in the morning and in the evening).

At the functional disturbances of cordial activity which are followed by tachycardia; a hyperthyroidism — on 50 mg 2 times a day (in the morning and in the evening).

Elderly patients are recommended to begin treatment with 50 mg/days.

The renal failure does not demand dose adjustment. At a liver failure dose adjustment depending on a clinical state can be required.

Features of use:

Use at pregnancy and in the period of a lactation. At pregnancy метопролол appoint according to strict indications if the estimated advantage for mother exceeds potential risk for a fruit (in connection with possible development in a fruit of bradycardia, arterial hypotension, a hypoglycemia). At the same time make careful observation, especially behind fetation. Strict observation of newborns during 48-72 h after delivery is necessary. If administration of drug is necessary in the period of a lactation, breastfeeding needs to be stopped.

Control of the patients accepting beta adrenoblockers includes heart-rate monitoring and arterial pressure (at the beginning of reception - daily, then 1 time in 3-4 months), concentration of glucose in blood at patients with diabetes (1 time in 4-5 months). It is necessary to train the patient in a technique of calculation of heart rate and to instruct about need of medical consultation at heart rate less than 50 beats/min.

Strengthening of expressiveness of allergic reactions (against the background of the burdened allergological anamnesis) and lack of effect of introduction of usual doses of Epinephrinum is possible. At elderly patients it is recommended to exercise control of function of kidneys (1 times in 4-5 months). Can strengthen symptoms of disturbance of peripheric arterial circulation. Drug withdrawal is carried out gradually, reducing a dose within 10 days. At arterial hypertension the effect occurs in 2-5 days, stable action is noted in 1-2 months.

At an angina of exertion the picked-up dose of drug has to provide heart rate at rest in limits 55-60ud/mines, at loading - not bolee110 to beats/min. At "smokers" efficiency of beta adrenoblockers is lower.

At a combination therapy with a clonidine reception of the last should be stopped in several days after cancellation of a metoprolol, in order to avoid hypertensive crisis. At a dose higher than 200 mg/days decrease cardioselectivity.

Metoprolol can mask some clinical displays of a thyrotoxicosis (for example, tachycardia). Sharp cancellation at patients with a thyrotoxicosis is contraindicated as it is capable to strengthen symptomatology.
At a diabetes mellitus can disguise the tachycardia caused by a hypoglycemia. Unlike non-selective beta adrenoblockers practically does not strengthen the hypoglycemia caused by insulin and recovery of concentration of glucose in blood to normal level does not detain.

In need of appointment to patients with bronchial asthma as the accompanying therapy use beta2-adrenostimulyator; at a pheochromocytoma - alpha adrenoblockers.

In need of carrying out surgical intervention it is necessary to warn the anesthesiologist about the carried-out therapy (the choice of medicine for the general anesthesia with the minimum negative inotropic effect), drug withdrawal is not recommended.

Reciprocal activation of n. vagus can be eliminated with intravenous administration of atropine (1-2 mg).

The medicines reducing stocks of catecholamines (for example, Reserpinum), can strengthen effect of beta adrenoblockers therefore the patients accepting such combinations of medicines have to be under constant observation of the doctor regarding detection of an excessive lowering of arterial pressure or bradycardia.

In case of emergence in patients of advanced age of the accruing bradycardia (less than 50 beats/min), arterial hypotension (systolic the ABP is lower than 100 mm hg), an atrioventricular block, a bronchospasm, ventricular arrhythmias, heavy abnormal liver functions and kidneys it is necessary to reduce a dose or to stop treatment. It is recommended to stop therapy at emergence of skin rashes and development of the depression caused by reception of beta adrenoblockers.

Drug withdrawal is carried out gradually, reducing a dose within 10 days. At the sharp termination of treatment there can be a syndrome of "cancellation" (strengthening of attacks of stenocardia, increase in arterial pressure). Special attention at drug withdrawal needs to be paid to patients with stenocardia.

The patients using contact lenses have to consider that against the background of treatment by beta adrenoblockers reduction of products of the lacrimal liquid is possible.

Influence on ability to manage vehicles and a difficult technique. During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

From a nervous system: increased fatigue, weakness, headache, delay of speed of mental and motor reactions. Paresthesias in extremities (at patients with the "alternating" lameness and Reynaud's syndrome), a tremor, spasms, a depression, concern, decrease in attention, drowsiness, sleeplessness, "dreadful" dreams, confusion of consciousness or short-term loss of memory, a hallucination, an adynamy, a myasthenia.

From sense bodys: seldom - decrease in sight, decrease in secretion of the lacrimal liquid, dryness and morbidity of eyes, conjunctivitis, a sonitus.

From cardiovascular system: sinus bradycardia, lowering of arterial pressure, orthostatic hypotension (dizziness, sometimes loss of consciousness). Seldom - decrease in contractility of a myocardium, development (aggravation) of chronic heart failure (hypostases, puffiness of feet and/or the lower part of shins, an asthma), disturbances of a heart rhythm, manifestation of a vasomotor spasm (strengthening of disturbance of peripheric circulation, a cold snap of the lower extremities, Reynaud's syndrome), disturbance of conductivity of a myocardium, a cardialgia. Very seldom - aggravation of earlier existing disturbances of atrioventricular conductivity.

From the alimentary system: nausea, vomiting, an abdominal pain, dryness of a mucous membrane of an oral cavity, locks or diarrhea, in some cases - an abnormal liver function (dark urine, yellowness of scleras or skin, a cholestasia), taste changes.

From integuments: urticaria, skin itch, rash, aggravation of a course of psoriasis, psoriazopodobny skin reactions, dermahemia, dieback, photosensitization, sweating strengthening, reversible alopecia.

From respiratory system: a nose congestion, a bronchospasm at appointment in high doses (loss of selectivity and/or at predisposed patients), an asthma.

From endocrine system: a hyperglycemia (at patients with a non-insulin-dependent diabetes mellitus), a hypoglycemia (at the patients receiving insulin), a hypothyroid state.

Allergic reactions: urticaria, skin itch, rash.

Laboratory indicators: thrombocytopenia (unusual bleedings and hemorrhages), agranulocytosis, leukopenia, increase in activity of "hepatic" enzymes, hyperbilirubinemia.

Influence on a fruit: pre-natal growth inhibition, hypoglycemia, bradycardia.

Others: a dorsodynia or joints, increase in body weight, decrease in a libido and/or potentiality, at the sharp termination of treatment - a syndrome of "cancellation" (strengthening of attacks of stenocardia, increase in arterial pressure).

Interaction with other medicines:

The allergens used for an immunotherapy or extracts of allergens for skin tests increase risk of emergence of heavy system allergic reactions or an anaphylaxis at the patients receiving метопролол. Iodinated X-ray contrast medicines for intravenous administration increase risk of development of anaphylactic reactions.

Phenytoinum at intravenous administration, medicines for inhalation general anesthesia (derivatives of hydrocarbons) increase expressiveness of cardiodepressive action and probability of a lowering of arterial pressure.

Changes efficiency of insulin and peroral hypoglycemic medicines, masks symptoms of the developing hypoglycemia (tachycardia, increase in arterial pressure).

Reduces clearance of lidocaine and xanthines (except Diphyllinum) and increases their concentration in plasma, especially at patients with initially increased clearance of theophylline under the influence of smoking.

Hypotensive effect non-steroidal anti-inflammatory drugs (Na delay + and blockade of synthesis of Pg kidneys) weaken, glucocorticosteroids and estrogen (Na+ delay).

Cardiac glycosides, Methyldopum, Reserpinum and гуанфацин, blockers of slow calcium channels (verapamil, diltiazem), Amiodaronum and other antiarrhytmic medicines increase risk of development or aggravation of bradycardia, atrioventricular blocks, cardiac standstills and heart failure. Nifedipine can lead to a considerable lowering of arterial pressure.

Diuretics, clonidine, sympatholytics, гидралазин, etc. can lead hypotensive medicines to an excessive lowering of arterial pressure.

Extends action of not depolarizing muscle relaxants and anticoagulating effect of coumarins.

Rub - and tetracyclic antidepressants, antipsychotic medicines (neuroleptics), ethanol, sedative and somnolent medicines strengthen oppression of the central nervous system.

Simultaneous use with monoamine oxidase inhibitors owing to considerable strengthening of hypotensive action is not recommended, having rummaged in treatment between reception of monoamine oxidase inhibitors and a metoprolola has to make not less than 14 days.

Not hydrogenated alkaloids of an ergot increase risk of development of disturbances of peripheric circulation.

Contraindications:

- hypersensitivity to a metoprolol or other components of drug, other beta adrenoblockers;
- cardiogenic shock;
- an atrioventricular block of the II-III degree (without artificial pacemaker);
- sinuatrial blockade;
- sick sinus syndrome;
- sinus bradycardia (heart rate less than 50 beats/min);
- chronic heart failure in a decompensation stage;
- Printsmetal's stenocardia;
- an acute myocardial infarction (heart rate less than 45 beats/min, R-Q interval more than 0,24 sec., systolic arterial pressure are less than 100 mm hg);
- lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption;
- concomitant use of monoamine oxidase inhibitors;
- simultaneous introduction of blockers of "slow" calcium channels (BMKK) like verapamil;
- age up to 18 years (efficiency and safety are not established);
- a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
- to the patients receiving long or intermittent therapy by inotropic means and acting on beta adrenoceptors.

With care. A diabetes mellitus, a metabolic acidosis, a renal failure (the clearance of creatinine (CC) less than 40 ml/min.), a myasthenia, an atrioventricular block of the I degree, a thyrotoxicosis, a depression (including and in the anamnesis), psoriasis, an abnormal liver function, allergic reactions in the anamnesis (increase in sensitivity to allergens, weighting of arterial hypertension and decrease in the therapeutic answer to Epinephrinum), advanced age, a chronic obstructive pulmonary disease, bronchial asthma, disturbances of peripheric circulation, a pheochromocytoma (is possible at simultaneous use of adrenoblockers).

Overdose:

Symptoms: the expressed heavy sinus bradycardia, dizziness, an atrioventricular block (up to development of total cross block and a cardiac standstill), a lowering of arterial pressure, unconscious states, arrhythmia, ventricular premature ventricular contraction, heart failure, cardiogenic shock, a cardiac standstill, a bronchospasm, a loss of consciousness, a coma, nausea, vomiting, cyanosis. The first signs of overdose are shown in 20 min.-2 the h after administration of drug.

Treatment: a gastric lavage and purpose of the adsorbing medicines; symptomatic therapy: at the expressed lowering of arterial pressure - the patient has to be in the provision of Trendelenburga; in case of an excessive lowering of arterial pressure, bradycardia and heart failure - intravenously, at an interval of 2-5 min., beta адреностимуляторы - before achievement of desirable effect or intravenously 0,5-2 mg of atropine. In the absence of positive effect - a dopamine, Dobutaminum or Norepinephrinum. At a hypoglycemia - introduction of 1-10 mg of a glucagon, installation of a transvenous intrakardialny electrostimulator. At a bronchospasm it is necessary to enter intravenously stimulators of beta2-adrenoceptors. At spasms - slow intravenous administration of diazepam. The hemodialysis is inefficient.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the places unavailable to children. A period of validity - 3 years. Not to apply after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 50 mg and 100 mg. On 10 tablets in a blister strip packaging. On 1, 2, 3, 5 or 10 blister strip packagings with the application instruction in a pack from a cardboard.