Metoprolol-Acrihin, tablets 50 mg 60 pcs

Metoprolol belongs to the cardioselective beta-adrenoceptor blockers with no intrinsic sympathomimetic activity and membrane stabilizing properties. It has hypotensive, antianginal and antiarrhythmic effects.

Blocking at low doses of beta₁-adrenoreceptors of the heart, it decreases catecholamine-stimulated cAMP formation from ATP, decreases intracellular calcium ion current, produces negative chrono-, dromo-, batmo- and inotropic effects (decreases heart rate, inhibits conduction and excitability, decreases myocardial contractility).

The total peripheral resistance at the beginning of beta-adrenoblockers use (in the first 24 hours after oral administration) – increases (as a result of reciprocal increase of alpha-adrenoreceptor activity and elimination of beta₂-adrenoreceptor stimulation) which returns to baseline after 1-3 days, and decreases with long-term use.

Hypotensive effect is caused by reflex reduction of cardiac output and renin synthesis, inhibition of renin-angiotensin-aldosterone system activity (it is more important in patients with initial renin hypersecretion) and central nervous system, restoration of aortic arch baroreceptors sensitivity (their activity in response to blood pressure decrease is not increased) and, finally, reduction of peripheral sympathetic effects.

Limits elevated BP at rest, during physical exertion and stress. The hypotensive effect is rapid (systolic BP decreases in 15 min, maximum in 2 hours) and lasts for 6 hours; diastolic BP changes slower: a stable decrease is observed after several weeks of regular use.

The antianginal effect is determined by decreasing myocardial oxygen demand as a result of HR shortening (prolongation of diastole and improvement of myocardial perfusion) and contractility and decreasing myocardial sensitivity to sympathetic innervation. It reduces the number and severity of angina attacks and increases exercise tolerance.

The antiarrhythmic effect is caused by the removal of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased content of CAMF, arterial hypertension), the decrease of spontaneous excitation rate of sinus and ectopic pacemakers and AV conduction slowing down (mainly in antegrade and, to smaller extent, in retrograde direction) through the AV node and through additional pathways.

In supraventricular tachycardia, atrial fibrillation, sinus tachycardia in functional heart disease and hyperthyroidism, decreases HR, or may even lead to restoration of sinus rhythm.

Prevent the development of migraine. When used in medium therapeutic doses, unlike non-selective beta-adrenoblockers, it has less pronounced effect on the organs containing beta₂-adrenoreceptors (pancreas, skeletal muscles, smooth muscle of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism. When used in high doses (more than 100 mg/day) it has a blocking effect on both beta-adrenoreceptor subtypes.

Indications

Active ingredient

Composition

How to take, the dosage

The tablets are taken orally with or immediately after a meal, not chewed, with a small amount of liquid.

Hypertension

The initial daily dose is 50-100 mg in 1-2 doses (morning and evening). In case of insufficient therapeutic effect, the daily dose may be gradually increased to 100-200 mg and/or additional prescription of other antihypertensive agents. The maximum daily dose is 200 mg.

Stenocardia, arrhythmias, prevention of migraine attacks

100-200 mg daily in two doses (morning and evening).

Secondary prevention of myocardial infarction

200 mg per day in two doses (morning and evening).

Hyperthyroidism

50 mg twice daily (morning and evening).

In elderly patients, in patients with renal dysfunction, and if hemodialysis is necessary, the dose is not changed. In patients with impaired liver function the dose of the drug should be reduced depending on the clinical condition.

Interaction

Combined use with MAO inhibitors is not recommended due to a significant increase in the hypotensive effect. Treatment interval between MAO inhibitors and metoprolol should be at least 14 days. Simultaneous intravenous administration of verapamil may provoke cardiac arrest. Concomitant administration of nifedipine leads to a significant decrease in blood pressure.

The agents for inhalation anesthesia (hydrocarbon derivatives) increase the risk of myocardial depression and arterial hypotension.

Beta-adrenomimetics, theophylline, cocaine, estrogens (sodium retention), indomethacin and other non-steroidal anti-inflammatory drugs (sodium retention and blocking of prostaglandin synthesis by the kidneys) weaken the hypotensive effect.

There is increased suppressive effect on the central nervous system – with ethanol; summation of the cardiodepressant effect – with anesthetics; increased risk of peripheral circulatory disorders – with ergot alkaloids.

When co-administered with hypoglycemic agents for oral administration, their effect may be reduced; with insulin – increased risk of hypoglycemia, increasing its severity and prolongation, masking some symptoms of hypoglycemia (tachycardia, sweating, increased blood pressure).

When combined with hypotensive agents, diuretics, nitroglycerin or “slow” calcium channel blockers, a sharp decrease of blood pressure may develop (special caution is necessary when combined with prazosin); increased severity of heart rate depression and suppression of atrioventricular conduction – when using metoprolol with verapamil, diltiazem, antiarrhythmic agents (amiodarone), reserpine, methyldopa, clonidine, guanfacine, agents for general anesthesia and cardiac glycosides. If metoprolol and clonidine are taken at the same time, then clonidine should be withdrawn after a few days if metoprolol is withdrawn (due to the risk of withdrawal).

Hepatic microsomal enzyme inducers (rifampicin, barbiturates) lead to increased metabolism of metoprolol and decreased plasma concentrations and reduced effect. Inhibitors (cimetidine, oral contraceptives, phenothiazines) – increase the plasma concentration of metoprolol.

Allergens used for immunotherapy or allergen extracts for skin testing when combined with metoprolol increases the risk of systemic allergic reactions or anaphylaxis; iodine containing x-ray contrast agents for IV administration increase the risk of anaphylactic reactions. Decreases clearance of xanthine (except diphylline), especially with initially increased clearance of theophylline due to smoking. Reduces lidocaine clearance, increases plasma concentration of lidocaine.

Enhances and prolongs the effect of antidepolarizing myorelaxants; prolongs the anticoagulant effect of coumarins.

The risk of significant BP decrease increases when co-administered with ethanol.

Special Instructions

Control of patients taking beta-adrenoblockers includes regular monitoring of HR and blood pressure, blood glucose content in diabetic patients. If necessary, for diabetic patients, the dose of insulin or hypoglycemic agents administered orally should be adjusted individually.

The patient should be instructed on how to calculate heart rate and instructed to consult a physician if the heart rate is less than 50 bpm. Dose above 200 mg per day decreases cardiac selectivity.

In heart failure, treatment with metoprolol is not started until the compensation stage is reached.

The severity of hypersensitivity reactions may be increased (with a history of allergic reactions) and no effect of the usual doses of epinephrine (adrenaline).

It may aggravate the symptoms of peripheral arterial circulatory disorders. The drug is withdrawn gradually, reducing the dose over 10 days. Abrupt discontinuation of treatment may cause “withdrawal” syndrome (increased angina pectoris attacks, increased blood pressure).

Particular attention should be paid to patients with angina pectoris when withdrawing the drug. In angina pectoris, the selected dose of the drug should provide a resting heart rate of 55-60 bpm, and not more than 110 bpm during exertion.

Patients who wear contact lenses should be aware that treatment with beta-adrenoblockers may decrease tear fluid production. Metoprolol may mask some clinical manifestations of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated because it can exacerbate the symptoms.

In diabetic patients may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-adrenoblockers, it practically does not increase insulin-induced hypoglycemia and does not delay the recovery of blood glucose concentration to normal levels.

When it is necessary to prescribe to patients with bronchial asthma, beta2-adrenomimetics are used as concomitant therapy; alpha-adrenoblockers are used in pheochromocytoma.

If it is necessary to perform surgical intervention it is necessary to warn the anesthesiologist about the therapy (choice of general anesthetic agent with minimal negative inotropic effect), cancellation of the drug is not recommended. Drugs that reduce catecholamine stores (e.g., reserpine) may increase the effect of beta-adrenoblockers, so patients taking such combinations of drugs should be under constant medical supervision for excessive reduction of blood pressure and bradycardia.

In elderly patients, regular monitoring of liver function is recommended. Adjustment of the dosing regimen is only required in elderly patients with increasing bradycardia (less than 50 bpm), marked BP decrease (systolic blood pressure below 100 mmHg), atrioventricular block, bronchospasm, ventricular arrhythmias, severe liver function abnormalities; sometimes therapy must be stopped.

Patients with severe renal insufficiency are advised to monitor renal function.

Patients with depressive disorders taking metoprolol should be monitored particularly; if depression develops as a result of taking beta-adrenoblockers, discontinuing therapy is recommended.

In the absence of sufficient clinical data, the drug is not recommended for use in children.

Impact on the ability to drive and operate machinery

In the beginning of treatment with metoprolol, patients may experience dizziness and fatigue. In this case they should refrain from driving motor transport and engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions. Thereafter, the safety of the dose is determined on an individual basis.

Features

Absorption when taken orally is complete (95%). Cmax in plasma is reached 1-2 hours after oral administration. T1/2 averages 3.5 h (range 1 to 9 h). It is subjected to intensive presystemic metabolism, bioavailability is 50% when administered for the first time and increases to 70% when administered repeatedly. Food intake increases bioavailability by 20-40%. Bioavailability of metoprolol increases in liver cirrhosis.

The binding to plasma proteins is 10%. It penetrates through the blood-brain and placental barriers. It penetrates into breast milk in small amounts.

Metabolized in the liver, 2 metabolites have beta-adrenoblocking activity. The CYP2D6 isoenzyme is involved in the metabolism of the drug. About 5% is excreted unchanged by the kidneys.

The treatment of patients with impaired renal function does not require adjustment of the drug dose. Impaired liver function slows down the metabolism of the drug and in cases of hepatic function insufficiency the dose of the drug should be reduced. It is not eliminated by hemodialysis.

Contraindications

Side effects

Central nervous system: increased fatigue, weakness, headache, slowed rate of mental and motor reactions; rarely – paresthesias in the extremities (in patients with “intermittent” claudication and Raynaud’s syndrome), depression, anxiety, reduced attention, sleepiness, insomnia, “nightmares” dreams, confusion or short-term memory loss, muscle weakness.

Sensory organs: rarely – decreased vision, decreased tear fluid secretion, dry and sore eyes, conjunctivitis, tinnitus.

Cardiovascular system disorders: sinus bradycardia, palpitations, decreased blood pressure, orthostatic hypotension (dizziness, sometimes loss of consciousness); rarely – decreased myocardial contractility, temporary aggravation of symptoms of chronic heart failure (edema, swelling of feet and/or lower shins, shortness of breath), arrhythmias, manifestation of angiospasm (increase in peripheral circulatory disorders, coldness of the lower extremities, Raynaud syndrome), myocardial conduction disorders.

Digestive system disorders: nausea, vomiting, abdominal pain, dry mouth, diarrhea, constipation, change in taste.

Skin disorders: urticaria, skin itching, rash, exacerbation of psoriasis, psoriasis-like skin reactions, skin hyperemia, exanthema, photodermatosis, increased sweating, reversible alopecia.

Respiratory system: nasal congestion, difficulty in exhaling (bronchospasm when prescribed in high doses – loss of selectivity and/or in predisposed patients), dyspnea.

Endocrine system: hypoglycemia (in patients receiving insulin); rarely – hyperglycemia (in patients with insulin-dependent diabetes).

Laboratory parameters: rare – thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia, increased liver enzymes activity, extremely rare – hyperbilirubinemia.

Fetal effects: possible intrauterine growth retardation, hypoglycemia, bradycardia.

Others: back or joint pain, as all beta-adrenoblockers in single cases may cause a slight increase in body weight, decreased libido and/or potency.

Overdose

Symptoms: severe sinus bradycardia, dizziness, nausea, vomiting, cyanosis, marked decrease in blood pressure, arrhythmia, ventricular extrasystole, bronchospasm, syncope, in acute overdose – cardiogenic shock, loss of consciousness, coma, atrioventricular block (up to development of complete transverse block and cardiac arrest), cardialgia.

The first signs of overdose occur 20 minutes to 2 hours after taking the drug.

Treatment: gastric lavage and adsorptive agents; symptomatic therapy: if there is a marked decrease in blood pressure – the patient should be in Trendelenburg position; in case of an excessive decrease in blood pressure, bradycardia and heart failure – IV, at intervals of 2-5 minutes, beta-adrenomimetics – until the desired effect is achieved or IV 0.5-2 mg of atropine sulfate. In the absence of a positive effect – dopamine, dobutamine or norepinephrine (noradrenaline).

As a follow-up, it is possible to administer 1-10 mg of glucagon, installation of transvenous intracardiac pacemaker. For bronchospasm, IV beta2-adrenomimetics should be administered. Metoprolol is poorly excreted by hemodialysis.

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