Metoprolol

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of a metoprolol of tartrate (in terms of 100% substance).

Excipients: sugar milk (lactose), starch potato grade "Extra", polyvinylpirrolidone (povidone) low-molecular medical, talc, croscarmellose sodium, magnesium stearate. 

The drug possessing hypotensive, anti-anginal and antiarrhytmic action.

Pharmacological properties:

Pharmacodynamics. Cardioselective beta1-adrenoblocker. Metoprolol possesses insignificant membrane stabilizing action and has no internal sympathomimetic activity. Blocking heart beta1-adrenoceptors, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosine triphosphoric acid (ATP), reduces intracellular current of calcium ions, 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 (GPVR) at the beginning of use of beta adrenoblockers (in the first 24 h after intake) 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 reflex reduction of minute volume of blood and synthesis of a renin, activity oppression the system renin-angiotensin-aldosteronovoy (SRAA) (has bigger value at patients with initial hypersecretion of a renin) and the central nervous system (CNS), recovery of sensitivity of baroreceptors of an aortic arch (there is no strengthening of their activity in response to a lowering of arterial pressure (ABP)) and as a result reduction of peripheral sympathetic influences. Reduces raised by the ABP at rest, at a physical tension and a stress.

The hypotensive effect develops quickly (systolic the ABP decreases in 15 min., as much as possible - in 2 h) and proceeds during 6 h, diastolic the ABP 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 ChSS urezheniye (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 the left zheyoludochk and increases in stretching of muscle fibers of ventricles can raise a potrebyonost in oxygen, especially at patients with the chronic heart failure (CHF).

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 (AV) carrying out (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 thyrotoxicosis urezhat ChSS or can even lead to recovery of a heart rhythm.

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 use in high doses (more than 100 mg/days) renders the blocking effect on both subtypes of beta adrenoceptors.

Pharmacokinetics. Absorption at intake full (95%). The maximum concentration in a blood plasma is reached in 1-2 hours after intake. The elimination half-life averages 3,5 h (ranging from 1 h to 9 h). Is exposed to intensive presistemny metabolism, bioavailability makes 50% at the first intake and increases up to 70% at repeated use. Meal increases bioavailability by 20-40%.

Bioavailability of a metoprolol increases at cirrhosis. Communication with proteins of a blood plasma of-10%. Gets through a blood-brain and placental barrier. Gets into breast milk in insignificant quantities. It is metabolized in a liver, 2 metabolites have beta and adrenoceptor blocking activity.

CYP2D6 isoenzyme takes part in metabolism of drug. About 5% of drug are removed in not changed look by kidneys. 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. Is not removed at a hemodialysis.

Indications to use:

- arterial hypertension (in monotherapy or in a combination with other anti-hypertensive means);

- 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:

Pill is taken inside along with meal or right after food, tablets can be halved (but not to chew) and to wash down with liquid.

Arterial hypertension - an initial daily dose makes 50 - 100 mg in 1-2 receptions (in the morning and in the evening). At insufficient therapeutic effect the daily dose can be gradually increased to 100 - 200 mg and/or additional purpose of other anti-hypertensive means. Maximum daily dose of 200 mg.

Secondary prevention of a myocardial infarction of 200 mg a day in two steps (in the morning and in the evening). Stenocardia, arrhythmias, prevention of attacks of migraine of 100 - 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 of 100 mg a day in two steps (in the morning and in the evening).

At a hyperthyroidism of 150-200 mg a day in 3-4 receptions. At elderly patients, at renal failures (KK less than 40 ml/min.), and also in need of carrying out a hemodialysis the dose is not changed. At the expressed abnormal liver functions the dose of drug should be lowered depending on a clinical state.

Features of use:

Control of the patients accepting beta adrenoblockers includes regular observation of ChSS and the ABP, concentration of glucose in blood at patients with 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. 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 (adrenaline) 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 ChSS at rest within 55-60 beats/min, at loading - no more than 110 beats/min. At "smokers" efficiency of beta adrenoblockers is lower. 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 value does not detain. In need of appointment to patients with bronchial asthma as the accompanying therapy use beta2-adrenomimetik; at a pheochromocytoma - alpha adrenoblockers.

In need of carrying out surgical intervention it is necessary to warn the anesthesiologist about reception of a metoprolol (the choice of means for the general anesthesia with the minimum otritsayotelny inotropic action), drug withdrawal is not recommended. Reciprocal activation of n.vagus can be eliminated in/in administration of atropine (1-2 mg). In case of the accruing bradycardia (less than 50 уд. / mines), arterial hypotension (systolic the ABP is lower than 100 mm hg), AV of blockade, 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.

At the sharp termination of treatment there can be a syndrome of "cancellation" (strengthening of attacks of stenocardia, increase in the ABP). 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. 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 the central nervous system: increased fatigue, weakness, headache, delay of speed of mental and motor reactions.

Seldom: paresthesias in extremities (at patients with "the alternating lameness" and Reynaud's syndrome), a depression, concern, decrease in concentration of attention, drowsiness, sleeplessness, "dreadful dreams", confusion of consciousness or short-term disturbance of memory, a myasthenia, hallucinations, an adynamy.

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

From cardiovascular system: a sinus bradycardia, heartbeat, the expressed decrease in the ABP, orthostatic hypotension (dizziness, sometimes a loss of consciousness). Seldom - decrease in sokratitelny ability of a myocardium, temporary aggravation of symptoms of chronic heart failure (puffiness of feet and/or the lower part of shins, an asthma), arrhythmias, manifestation of a vasomotor spasm (strengthening of disturbance of peripheric circulation, a poyokholodaniye of the lower extremities, Reynaud's syndrome), a cardialgia; very seldom - aggravation of earlier existing disturbances of AV of conductivity.

From the alimentary system: nausea, vomiting, abdominal pain, dryness of a mucous membrane of an oral cavity, diarrhea, lock, taste change, hepatitis.

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

From endocrine system: a hypoglycemia (at the patients receiving insulin), it is rare: a hyperglycemia (at patients with a diabetes mellitus), a hypothyroidism.

From respiratory system: rhinitis, a bronchospasm, an asthma at physical effort.

Others: a dorsodynia or joints, the arthralgia, as well as all beta adrenoblockers in isolated cases can cause insignificant increase in body weight, decrease in a libido and/or potentiality.

Interaction with other medicines:

Simultaneous use with inhibitors of a monoaminooxidase (MAO) owing to considerable strengthening of hypotensive action is not recommended. Having rummaged in treatment between reception of MAO inhibitors and a metoprolola has to make not less than 14 days.

Simultaneous in/in administration of verapamil can provoke a cardiac standstill. Co-administration of nifedipine leads to considerable decrease in the ABP.

Means for an inhalation anesthesia (halogenated hydrocarbons) increase risk of oppression of function of a myocardium and development of arterial hypotension; summation of cardiodepressive effect - with means for the general anesthesia is noted; increase in expressiveness of an urezheniye of ChSS and oppression of AV of conductivity - at use of a metoprolol with verapamil, diltiazem, antiarrhytmic means (Amiodaronum), Reserpinum, metildopy, a clonidine, guanfatsiny, means for the general anesthesia and cardiac glycosides.

Beta-adrenergic agonists, theophylline, cocaine, etrogena (a delay of ions of sodium), indometacin and other non-steroidal anti-inflammatory drugs (a delay of sodium and blocking of synthesis of prostaglandins kidneys) weaken hypotensive effect.

Rub - and tetracyclic antidepressants, antipsychotic means (neuroleptics), sedative and hypnagogues strengthen oppression of TsNS.

Strengthening of the oppressing action on TsNS - with ethanol is noted; increase in risk of disturbances of peripheric circulation - with ergot alkaloids.

At joint reception 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 lengthening, masking of some symptoms of a hypoglycemia (tachycardia, perspiration, increase in arterial pressure).

At a combination to antihypertensives, diuretics, nitroglycerine or blockers of "slow" calcium channels sharp decrease in the ABP can develop, the special ostoyorozhnost is necessary at a combination to Prazozinum. 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 of microsomal enzymes of a liver (Cimetidinum, oral contraceptives, fenotiazina) - increase concentration of a metoprolol in a blood plasma.

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 X-ray contrast means for in/in introductions increase risk of development of anaphylactic reactions.

Reduces clearance of xanthines (except a diprofillin), especially 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 not depolarizing muscle relaxants; extends anticoagulating effect of derivatives of coumarin.

At combined use with ethanol the risk of the expressed decrease in the ABP increases.

The means 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 identification of excessive decrease in the ABP or bradycardia.

Contraindications:

- hypersensitivity to a metoprolol or other components of drug, other beta adrenoblockers;
- cardiogenic shock;
- AV blockade of the II-III degree (without artificial pacemaker);
- sinuatrial blockade;
- sick sinus syndrome;
- the expressed bradycardia;
- chronic heart failure in a decompensation stage;
- Printsmetal's stenocardia;
- acute myocardial infarction (ChSS less than 45 уд. / mines, PQ interval more than 0,24 sec., systolic ABP less than 100 mm hg);
- lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption;
- the lactation period (see the section "Pregnancy and Period of a Lactation");
- simultaneous intravenous administration of blockers of "slow" calcium channels (BMKK) like verapamil (see the section "Interaction with Other Medicinal Sredyostvo");
- 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, AV blockade of the I degree, тиреотокси­коз, a depression (including and in the anamnesis), psoriasis, an abnormal liver function, allergic reyoaktion in the anamnesis (increase in sensitivity to allergens, weighting of arteriyoalny hypertensia and decrease in the therapeutic answer to adrenaline), advanced age, a chronic obstructive pulmonary disease, bronchial asthma, disturbances of peripheric circulation, a pheochromocytoma (is possible at simultaneous use of alpha adrenoblockers).

Overdose:

Symptoms: the expressed sinus bradycardia, dizziness, nausea, vomiting, cyanosis, the expressed decrease in the ABP, arrhythmia, a ventricular ekstasistoliya, a bronchospasm, a syncope, at acute overdose - cardiogenic shock, a loss of consciousness, a coma, AV (up to development of total cross block and a cardiac standstill), spasms, an apnoea. The first signs of overdose are shown in 20 min. - the 2nd hour after administration of drug.

Treatment: a gastric lavage and reception of the adsorbing means; symptomatic therapy: at the expressed decrease in the ABP - the patient has to be in the provision of Trendelenburga; in case of excessive decrease in the ABP, bradycardia and heart failure - in/in, at an interval of 2-5 min., beta адреномиметики - 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, introduction of 1-10 mg of a glucagon, statement of an artificial pacemaker. At a bronchospasm it is necessary to enter into beta2-adrenomimetik. The hemodialysis is inefficient.

Storage conditions:

List B. In the dry, protected from light place at a temperature not above 25 °C. In the place, unavailable to children, the Period of validity 3 years. Not to use 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. 3 blister strip packagings together with the application instruction place in a pack from a cardboard.