Metoprolol

General characteristics. Structure:

Active agent: a metoprolola tartrate - 100,0 mg.

Excipients: lactoses monohydrate (sugar milk) - 180,0 mg, cellulose microcrystallic - 72,0 mg potato starch - 12,0 mg, mg sodium-16,0 carboxymethylstarch, povidone (polyvinylpirrolidone) - 16,0 mg, magnesium stearate - 4,0 mg.

Pharmacological properties:

Pharmacodynamics. The cardioselective blocker of r-adrenoceptors, has insignificant membrane stabilizing effect and has no internal sympathomimetic activity. Possesses anti-hypertensive, anti-anginal and antiarrhytmic action. Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions (Sa2+), renders negative hrono-, dromo-, batmo-and inotropic action (urezhat the heart rate (HR), conductivity and excitability oppresses, reduces contractility of a myocardium). The general peripheric vascular resistance 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 value decreases. Anti-hypertensive action is caused by reduction of cordial emission and synthesis of a renin, activity oppression the system renin-angiotensin-aldosteronovoy (SRAA) (is of great importance 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 (AP) at rest, at a physical tension and a stress. 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. Arterial pressure decreases in 15 min., as much as possible - in 2 hours and proceeds during 6 h, diastolic arterial pressure changes more slowly: stable decrease is observed after several weeks of regular reception.
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 conductivity (it is preferential in antegrade and, to a lesser extent, in retrograde the directions through an AV node) and on additional ways. At supraventricular tachycardia, atrial fibrillation, sinus tachycardia at functional heart diseases and a hyperthyroidism, urezhat heart rate, or can even lead to recovery of a sinoatrial rate. Prevents development of migraine. At use in average therapeutic doses, unlike non-selective beta adrenoblockers, 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. 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 Absorption. At intake метопролол it is almost completely absorbed (about 95%) from digestive tract. Meal increases bioavailability for 20-40%. Is exposed to intensive presistemny metabolism therefore system bioavailability makes about 35%. The maximum concentration in a blood plasma is reached in 1,5-2 hours after intake.

Distribution. Communication with proteins of a blood plasma of 12%. The volume of distribution makes 5,6 l/kg. Gets through a blood-brain and placental barrier. It is allocated in breast milk in insignificant quantities.

Metabolism. Metoprolol is almost completely metabolized in a liver, generally with the participation of CYP2D6 isoenzyme. The elimination half-life makes from 3 to 4 hours, however at patients with "slow" metabolism can increase till 7-8 o'clock. Metabolites about-desmetilmetoprolol and and-gidroksimetoprolol have weak beta and adrenoceptor blocking activity.

Removal. It is removed preferential by kidneys (about 95%), about 10% are removed in not changed look. It is not removed at a hemodialysis.
At patients with cirrhosis and a porto-caval anastomosis bioavailability increases, and the clearance decreases. At patients with a porto-caval anastomosis of AUC (the area under a curve "concentration time") can increase by 6 times, and the clearance can decrease to 0,3 ml/min.

Indications to use:

• arterial hypertension (in monotherapy or in a combination with other hypotensive drugs);
• the functional disturbances of cordial activity which are followed by tachycardia;
• coronary heart disease: a myocardial infarction (secondary prevention - complex therapy), prevention of attacks of stenocardia;
• disturbances of a heart rhythm (supraventricular tachycardia; ventricular premature ventricular contraction);
• hyperthyroidism (complex therapy);
• prevention of attacks of migraine.

Route of administration and doses:

Drug Metoprolol should be accepted inside, in time or right after meal, tablets can be halved (but not to chew) and to wash down with liquid. Arterial hypertension:
The initial daily dose makes 50-100 mg in 1-2 receptions (in the morning and in the evening) (1/2 tablets on 100 mg - 1 tablet). At insufficient therapeutic effect the daily dose can be raised to 100-200 mg or in addition use other hypotensive drugs. The maximum daily dose - 200 mg.
At arrhythmia, for prevention of attacks of stenocardia and migraine:
100-200 mg a day in two steps (in the morning and in the evening). Secondary prevention of a myocardial infarction: 200 mg a day in two steps (in the morning and in the evening). The functional disturbances of cordial activity which are followed by tachycardia: 100 mg a day in two steps (in the morning and in the evening). At a hyperthyroidism - on 150-200 mg a day in 2 receptions (in the morning and in the evening).
Elderly patients are recommended to begin treatment with 50 mg (1/2 tablets on 100 mg) in days.
At renal failures dose adjustment is not required. At a liver failure dose adjustment depending on a clinical condition of the patient can be required. If there is a need to interrupt or stop treatment by drug Metoprolol after long therapy, the dosage of drug has to be gradually reduced twice within at least 2 weeks.
At emergence of a syndrome of "cancellation" the dose decline has to occur more slowly. The sharp termination of administration of drug can cause ischemia of a myocardium and can lead to an aggravation of a course of stenocardia or a myocardial infarction, and also to strengthen arterial hypertension.

Features of use:

The patients accepting beta adrenoblockers should not enter intravenously blockers of "slow" calcium channels like verapamil.
Control of a condition of the patients accepting beta adrenoblockers includes regular heart-rate monitoring (ChSS) and the arterial pressure, concentration of glucose of blood at patients a diabetes mellitus. If necessary, for patients with a diabetes mellitus, the dose of insulin or the hypoglycemic means appointed inside should be picked up individually.
It is necessary to train the patient in a technique of calculation of ChSS and to instruct about need of medical consultation at ChSS less than 50 уд. / min. At reception of a dose higher than 200 mg a day decrease cardioselectivity. At heart failure treatment by Metoprolol is begun only after achievement of a stage of compensation.
To patients with Printsmetal's stenocardia, it is not recommended to appoint non-selective beta adrenoblockers. Strengthening of expressiveness of reactions of hypersensitivity (against the background of the burdened allergological anamnesis) and lack of effect of introduction of usual doses of Epinephrinum (adrenaline) is possible.
At the patients accepting beta adrenoblockers, the acute anaphylaxis proceeds in more severe form. Can strengthen symptoms of disturbance of peripheric arterial circulation. Drug withdrawal is carried out gradually, reducing a dose within 14 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.
At an angina of exertion the picked-up dose of drug has to provide heart rate at rest within 55-60 beats/min, at loading - no more than 110 beats/min. 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. Metoprolol can mask some clinical manifestations of a hyperthyroidism (for example, tachycardia). Sharp cancellation at patients with a thyrotoxicosis is contraindicated as it is capable to strengthen symptomatology.
At a diabetes mellitus can mask 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 of blood to normal level does not detain. In need of appointment to patients with bronchial asthma, as the accompanying therapy therapy beta2-adrenomimetiky has to be appointed. It is necessary to appoint minimum effective dose of a metoprolol, at the same time increase in a dose of a beta2-adrenomimetik can be required. Patients with a pheochromocytoma, in parallel with drug Me-toprolol, should appoint alpha adrenoblocker. In need of carrying out surgical intervention it is necessary to warn the anesthesiologist about the carried-out therapy (the choice of means for the general anesthesia with the minimum negative inotropic effect), drug withdrawal is not recommended.
It is necessary to avoid purpose of high doses of Metoprolol without preliminary titration to the patients who are exposed to not cardiological operations as at patients with factors of cardiovascular risk it was associated with bradycardia, arterial hypotension and a stroke, including from the death at once.
The drugs reducing stocks of catecholamines (for example, Reserpinum), can strengthen effect of beta adrenoblockers therefore the patients accepting such combinations of drugs have to be under constant observation of the doctor regarding detection of an excessive lowering of arterial pressure or bradycardia.
At elderly patients it is recommended to exercise control of function of a liver regularly. Correction of the mode of dosing is required only in case of emergence in patients of advanced age of the accruing bradycardia (less than 50 уд. / mines), the expressed decrease in the ABP (systolic arterial pressure is lower than 100 mm hg), an atrioventricular block, a bronchospasm, ventricular arrhythmias, heavy abnormal liver functions. Sometimes it is necessary to stop treatment.
Patients with a heavy renal failure are recommended to exercise control of function of kidneys.
It is necessary to carry out special control of a condition of patients with the depressive frustration accepting Metoprolol; in a case development of the depression caused by reception of beta adrenoblockers it is recommended to stop therapy.

INFLUENCE ON ABILITY of CONTROL of MOTOR TRANSPORT AND to WORK WITH MECHANISMS during therapy it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Frequency of development of side effects is classified according to recommendations of World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; seldom - not less than 0,01%, but less than 0,1%; very seldom - less than 0,01%.
- From the hemopoietic system: very seldom - thrombocytopenia, a leukopenia.
- From cardiovascular system: often - the sinus bradycardia, postural disturbances (which are very seldom followed by a faint), "cold snap" of extremities, a heart consciousness; infrequently - temporary strengthening of symptoms of heart failure, an atrioventricular block of the I degree; cardiogenic shock at patients with an acute myocardial infarction, peripheral hypostases, pains in heart; seldom - other disturbances of conductivity of a myocardium, arrhythmia; very seldom - gangrene at patients with the previous heavy disturbances of peripheric circulation.
- From a nervous system: very often - increased fatigue; often - a headache, dizziness; infrequently - paresthesias, spasms, a depression, decrease in concentration of attention, drowsiness or sleeplessness, nightmares; seldom - the increased nervous irritability, uneasiness, impotence / sexual dysfunction, Peyroni's disease; very seldom - memory amnesia/disturbance, depression, hallucinations.
- From sense bodys: seldom - vision disorders, dryness and/or irritation of eyes, conjunctivitis, a hearing disorder and noise
in ears.
- From the alimentary system: often - nausea, abdominal pains, diarrhea, a lock; infrequently - vomiting; seldom - dryness of a mucous membrane of an oral cavity; very seldom - disturbance of flavoring feelings.
- From a liver: seldom - abnormal liver functions, increase in activity of "hepatic" transaminases; very seldom - hepatitis.
- From integuments: infrequently - a small tortoiseshell, the increased sweating; seldom - an alopecia; very seldom - a photosensitization, an aggravation of a course of psoriasis.
- From respiratory system: often - an asthma at physical effort; infrequently - a bronchospasm; seldom - rhinitis.
- From endocrine system: seldom - hypo - a hyperglycemia at patients a diabetes mellitus of 1 type, masking of symptoms of a thyrotoxicosis.
- From a musculoskeletal system: very seldom - an arthralgia.
- From a metabolism: infrequently - increase in body weight; seldom - aggravation of a current of a latentnoprotekayushchy diabetes mellitus.
- Laboratory indicators: very seldom - decrease in concentration of cholesterol of high density and increase in triglycerides in a blood plasma.

Interaction with other medicines:

Simultaneous use with inhibitors of a monoaminooxidase (MAO) owing to considerable strengthening of anti-hypertensive action is not recommended. Having rummaged in treatment between reception of MAO inhibitors and a metoprolola has to make not less than 14 days.
Beta адреностимуляторы, theophylline, cocaine, estrogen (a sodium delay), indometacin and other non-steroidal anti-inflammatory drugs (a delay of sodium and blocking of synthesis of prostaglandin kidneys) weaken antigipertenziv-ny effect of a metoprolol.
At simultaneous use with hypoglycemic means for intake decrease in their effect is possible; with insulin - increase in risk of development of a hypoglycemia, strengthening of its expressiveness and duration, masking of some symptoms of a hypoglycemia (tachycardia, the increased sweating, increase in arterial pressure). At simultaneous use with antihypertensives, diuretics, inhibitors of an angiotensin-converting enzyme, nitroglycerine or blockers of "slow" calcium channels the sharp lowering of arterial pressure can develop (extra care is necessary at a combination to Prazozinum); the risk of bradycardia at a combination with meflokhiny increases; the expressed decrease in the ABP and bradycardia at a combination to Epinephrinum; the expressed urezheny ChSS and oppression of atrioventricular conductivity up to a total block - at use of a metoprolol with verapamil, diltiazem, Reserpinum, metildopy, a clonidine, guanfatsiny and cardiac glycosides, means for the general anesthesia (along with cardiodepressive and anti-hypertensive effects). Simultaneous in/in administration of verapamil can provoke a cardiac standstill.
The medicines inducing or inhibiting CYP2D6 isoenzyme can exert impact on concentration of a metoprolol in a blood plasma. Concentration of a metoprolol can increase in a blood plasma at a concomitant use with other drugs which are substrate for CYP2D6 isoenzyme, for example, antiarrhytmic drugs, antihistaminic drugs, antagonists of H2 receptors, antidepressants (selective serotonin reuptake inhibitors, for example, пароксетин, fluoxetine, sertraline), neuroleptics and inhibitors of cyclooxygenase-2. Antiarrhytmic drugs I of a class can lead to summing of a negative inotropic effect with development of the expressed hemodynamic side effects in patients with dysfunction of a left ventricle (it is necessary to avoid this combination at patients with a sick sinus syndrome and disturbance of atrioventricular conductivity). Quinidine inhibits metabolism of a metoprolol at patients with "bystry" metabolism, leading to substantial increase of concentration of a metoprolol in a blood plasma and to strengthening of its beta and adrenoceptor blocking action.
The combination to Amiodaronum increases risk of development of the expressed sinus bradycardia (including through long time after cancellation of Amiodaronum, owing to its long elimination half-life).
If метопролол and the clonidine is accepted at the same time, then at cancellation of a metoprolol the clonidine is cancelled in several days (in connection with risk of emergence of a syndrome of "cancellation"). Inductors of microsomal enzymes of a liver (rifampicin, barbiturates) lead to strengthening of metabolism of a metoprolol, to decrease in concentration of a metoprolol in a blood plasma and to reduction of effect. Inhibitors (Cimetidinum, oral contraceptives, fenotiazina) - increase concentration of a metoprolol in a blood plasma.
Difengidramin reduces clearance of a metoprolol, strengthening its action.
Simultaneous use with high doses of a fenilpropa-nolamin can lead to paradoxical increase in the ABP (up to hypertensive crisis). The allergens used for an immunotherapy or extracts of allergens for skin tests at combined use with metoprololy, increase risk of emergence of system allergic reactions or an anaphylaxis; iodinated radiopaque substances for in/in introductions increase risk of development of anaphylactic reactions. Reduces clearance of xanthines (except Diphyllinum), especially at patients with initially increased clearance of theophylline under the influence of smoking. Reduces clearance of lidocaine, increases concentration of lidocaine in a blood plasma.
Strengthens and prolongs action of the anti-depolarizing muscle relaxants; extends anti-coagulative effect of coumarins. At combined use with the anxiolytics and drugs having somnolent activity, the anti-hypertensive effect amplifies, with ethanol - the risk of the expressed decrease in the ABP increases and the oppressing action on the central nervous system amplifies.
Increase in risk of disturbances of peripheric circulation - with ergot alkaloids is noted.

Contraindications:

• hypersensitivity to a metoprolol or to other ingredients of drug;
• lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption;
cardiogenic shock;
atrioventricular block (AV) II and III of degree (without artificial pacemaker); sinuatrial blockade; sick sinus syndrome;
the expressed bradycardia (the heart rate (HR) less than 50 уд. / mines);
heavy disturbances of peripheric circulation; heart failure in a decompensation stage; hyperreactivity of bronchial tubes (for example, at heavy bronchial asthma to the patients receiving continuous or intermittent therapy by the inotropic drugs operating on beta adrenoceptors, a chronic obstructive pulmonary disease (HOBL) in an aggravation stage);
• Printsmetal's stenocardia;
• arterial hypotension (in case of use at secondary prevention of a myocardial infarction - systolic the ABP less than 100 mm hg);
• at suspicion of an acute myocardial infarction (ChSS less than 45 уд. / min., PQ interval more than 0,24 sec. or systolic the ABP less than 100 mm hg);
• a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
• breastfeeding period;
• simultaneous intravenous administration of blockers of "slow" calcium channels like verapamil (see the section "Interaction with Other Medicines");
• a concomitant use of inhibitors of a monoaminooxidase (MAO) (see the section "Interaction with Other Medicines");
• age up to 18 years (efficiency and safety are not established).

WITH CARE
(see also section "Special Instructions") - a diabetes mellitus, a metabolic acidosis, an abnormal liver function and/or kidneys (the clearance of creatinine (CC) less than 40 ml/min.), a myasthenia, AV blockade of the I degree, a thyrotoxicosis, a depression (including in the anamnesis), psoriasis, allergic reactions in the anamnesis (increase in sensitivity to allergens, weighting of arterial hypertension and decrease in the therapeutic answer to adrenaline is possible), bronchial asthma, a chronic obstructive pulmonary disease, emphysema of lungs, chronic obstructive bronchitis, obliterating diseases of peripheral vessels (the "alternating" lameness, Reynaud's syndrome), advanced age.

USE AT PREGNANCY AND DURING FEEDING BY THE BREAST
At pregnancy Metoprolol appoint only 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). Beta adrenoblockers reduce permeability of a placenta that can lead to premature birth or pre-natal death of a fruit.
The risk of complications from heart and lungs increases in a puerperal period at those newborns whose mothers received метопролол. Administration of drug should be stopped for 48-72 h before childbirth. When it is impossible, it is necessary to provide strict observation of newborns during 48-72 h after the birth.
Metoprolol is allocated in breast milk. The children who are on breastfeeding have to be under medical control in connection with possible development of symptoms of blockade of beta adrenoceptors.
In need of drug use Metoprolol breastfeeding is recommended to cancel.

Overdose:

Symptoms: the expressed sinus bradycardia, dizziness, nausea, vomiting, cyanosis, the expressed lowering of arterial pressure, arrhythmia, ventricular premature ventricular contraction, a bronchospasm, a syncope, at acute overdose - cardiogenic shock, a loss of consciousness, a coma, an atrioventricular block (up to development of total cross block and a cardiac standstill), a cardialgia, a hypoglycemia, a hyperpotassemia, spasms, an apnoea.
The first signs of overdose are shown in 20 min.-2 the h after administration of drug. At overdose or the menacing decrease in ChSS and/or arterial pressure treatment by drug Metoprolol needs to be stopped immediately.

Treatment: a gastric lavage and purpose of the adsorbing means; 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 - in/in, at an interval of 2-5 min., beta-adrenergic agonists - before achievement of desirable effect or in/in 0,5-2 mg of atropine. In the absence of positive effect - a dopamine, Dobutaminum or Norepinephrinum (noradrenaline).
As the subsequent measures, perhaps, statement of an artificial pacemaker. At a bronchospasm it is necessary to enter into beta2-adrenomimetik. Metoprolol is badly brought by means of a hemodialysis.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 100 mg.
On 10, 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 tablets in a container polymeric for medicines.
One container or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 blister strip packagings together with the application instruction place in a pack from a cardboard.