Metoprolol

Pharmacodynamics

Metoprolol refers to cardioselective β-adrenergic receptor blockers that do not have internal sympathomimetic activity and membrane-stabilizing properties. It has hypotensive, antianginal and antiarrhythmic effects. Blocking β-adrenergic receptors of the heart in low doses, it reduces the formation of cAMP stimulated by catecholamines from ATP, reduces the intracellular Ca2 + current, has a negative chrono-, dromo-, batmo- and inotropic effect (reduces the heart rate, inhibits conduction and excitability, reduces myocardial contractility). The total peripheral resistance at the beginning of the use of β-adrenergic blockers (in the first 24 hours after oral administration) - increases (as a result of a reciprocal increase in the activity of α-adrenergic receptors and the elimination of β-adrenergic receptor stimulation), which returns to the initial one after 1-3 days, and with prolonged appointment - is reduced. The acute antihypertensive effect is due to a decrease in cardiac output, a stable antihypertensive effect develops within 2-3 weeks and is caused by a decrease in renin synthesis, and accumulation of plasma renin, inhibition of the renin-angiotensin system activity (of great importance in patients with initial renin hypersecretion) and CNS restoration of sensitivity baroreceptors of the aortic arch (there is no increase in their activity in response to a decrease in blood pressure) and, as a result, a decrease in peripheral sympathetic influences. Reduces elevated blood pressure at rest, with physical exertion and stress. The antianginal effect is determined by a decrease in myocardial oxygen demand as a result of a decrease in heart rate (lengthening diastole and improved myocardial perfusion) and contractility, as well as a decrease in the sensitivity of the myocardium to the effects of sympathetic innervation. Reduces the number and severity of angina attacks and increases exercise tolerance. Blood pressure decreases after 15 minutes, as much as possible after 2 hours and lasts for 6 hours, diastolic blood pressure changes more slowly: a stable decrease is observed after several weeks of regular use. The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased content of cAMP, arterial hypertension), a decrease in the rate of spontaneous excitation of sinus and ectopic pacemakers, and a slowdown in AV conduction (mainly in antegrade and, to a lesser extent, in retrograde directions) via the AV node) and additional paths. With supraventricular tachycardia, atrial fibrillation, sinus tachycardia with functional heart diseases and hyperthyroidism, it reduces the heart rate, or can even lead to the restoration of sinus rhythm. Prevents the development of migraine. When used in medium therapeutic doses, unlike non-selective beta-blockers, it has a less pronounced effect on organs containing β-adrenergic receptors (pancreas, skeletal muscle, smooth muscles of the peripheral arteries, bronchi and uterus) and on carbohydrate metabolism. When used in large doses (more than 100 mg / day) it has a blocking effect on both subtypes of β-adrenergic receptors.

Pharmacokinetics

Metoprolol is rapidly and almost completely (95%) absorbed in the digestive tract. Cmax in blood plasma is achieved 1-2 hours after ingestion. T1 / 2 averages 3.5 hours (ranging from 1 hour to 9 hours). Bioavailability is 50% at the first dose and increases to 70% with repeated use. Eating increases bioavailability by 20-40%. The bioavailability of metoprolol increases with cirrhosis. Communication with plasma proteins on average 10%. The drug crosses the blood-brain and placental barriers. It is excreted in breast milk in small amounts. Metabolized in the liver. Metabolites do not have pharmacological activity. About 5% of the drug is excreted unchanged by the kidneys. Treatment of patients with reduced renal function does not require dose adjustment. Impaired liver function slows down the metabolism of the drug, and in cases of insufficient liver function, the dose of the drug should be reduced. Not removed by hemodialysis.

Contraindications

cardiogenic shock; AV block II-III degree; sinoatrial (SA) block; sick sinus syndrome; severe bradycardia; decompensated heart failure; Prinzmetal's angina pectoris; arterial hypotension (in case of use for secondary prevention of myocardial infarction - systolic blood pressure less than 100 mm Hg, heart rate less than 45 beats / min); simultaneous administration of MAO inhibitors or simultaneous iv administration of verapamil; lactation period; age up to 18 years (effectiveness and safety have not been established); hypersensitivity to metoprolol or other components of the drug, other beta-blockers. With caution - diabetes mellitus, metabolic acidosis, bronchial asthma, chronic obstructive pulmonary disease (pulmonary emphysema, chronic obstructive bronchitis), peripheral vascular disease obliterans (intermittent claudication, Raynaud's syndrome), chronic liver and / or renal failure, myasthenia gravis, pheochromocytoma, AV -blockade of I degree, thyrotoxicosis, depression (including a history), psoriasis, pregnancy, old age.

Pregnancy and lactation

During pregnancy, it is prescribed according to strict indications, taking into account the benefit / risk ratio (due to the development of the fetus bradycardia, arterial hypotension, hypoglycemia). In this case, close monitoring is carried out, especially for the development of the fetus. It is necessary to strictly monitor newborns within 48-72 hours after delivery. The effect of metoprolol on a newborn, while breastfeeding has not been studied, therefore, women taking metoprolol should stop breast-feeding.

Side effects

Side effects depend on the individual sensitivity of the patient. Usually they are insignificant and disappear after discontinuation of the drug. From the nervous system: increased fatigue, weakness, headache, slowing down the speed of mental and motor reactions; rarely - paresthesia in the extremities (in patients with intermittent claudication and Raynaud's syndrome), depression, anxiety, decreased attention, drowsiness, insomnia, nightmares, confusion or short-term memory impairment, muscle weakness. On the part of the sensory organs: rarely - decreased vision, decreased secretion of tear fluid, dryness and soreness of the eyes, conjunctivitis, tinnitus. From the cardiovascular system: sinus bradycardia, palpitations, decreased blood pressure, orthostatic hypotension, dizziness, sometimes loss of consciousness); rarely - decreased myocardial contractility, a temporary aggravation of the symptoms of chronic heart failure (edema, swelling of the feet and / or lower legs, shortness of breath), arrhythmias, the manifestation of angiospasm (increased peripheral blood circulation disturbance, cooling of the lower extremities, Raynaud's syndrome), myocardial conduction disturbance, cardialgia . From the digestive system: nausea, vomiting, abdominal pain, dry mouth, diarrhea, constipation, impaired liver function, taste change. From the skin: urticaria, pruritus, rash, exacerbation of psoriasis, psoriasis-like skin reactions, flushing of the skin, exanthema, photodermatosis, increased sweating, reversible alopecia. From the respiratory system: nasal congestion, difficulty breathing out (bronchospasm when prescribed in high doses - loss of selectivity and / or in predisposed patients), shortness of breath. From the endocrine system: hypoglycemia (in patients receiving insulin), rarely: hyperglycemia (in patients with diabetes mellitus), hypothyroidism. Laboratory indicators: rarely - thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia, increased activity of liver enzymes; extremely rarely - hyperbilirubinemia. Effect on the fetus: intrauterine growth retardation, hypoglycemia, bradycardia are possible. Other: pain in the back or joints, like all beta-blockers in rare cases, can cause a slight increase in body weight, decreased libido and / or potency.

Interaction

The simultaneous use with MAO inhibitors is not recommended due to a significant increase in the hypotensive effect. A break in treatment between taking MAO inhibitors and metoprolol should be at least 14 days. The simultaneous iv administration of verapamil can cause cardiac arrest. The simultaneous administration of nifedipine leads to a significant decrease in blood pressure. Means for inhalation anesthesia (hydrocarbon derivatives) increase the risk of inhibition of myocardial function and the development of arterial hypotension. Beta-adrenostimulants, theophylline, cocaine, etrogens (sodium retention), indomethacin and other NSAIDs (sodium retention and blocking prostaglandin synthesis by the kidneys) weaken the hypotensive effect. Tri- and tetracyclic antidepressants, antipsychotic drugs (antipsychotics), sedative and hypnotic drugs increase central nervous system depression. There is an increase in the inhibitory effect on the central nervous system - with ethanol; summation of the cardiodepressive effect - with anesthesia; increased risk of peripheral circulation disorders - with ergot alkaloids. When combined with hypoglycemic agents for oral administration, a decrease in their effect is possible; with insulin - an increased risk of developing hypoglycemia, an increase in its severity and lengthening, masking of some symptoms of hypoglycemia (tachycardia, sweating, increased blood pressure). When combined with antihypertensive drugs, diuretics, nitroglycerin or slow calcium channel blockers, a sharp decrease in blood pressure may develop); special caution is necessary when combined with prazosin); an increase in the severity of heart rate reduction and inhibition of AV conduction - with the use of metoprolol with verapamil, diltiazem, antiarrhythmic drugs (amiodarone), reserpine, alpha-methyl dopa, clonidine, guanfacine, general anesthesia and cardiac glycosides. If metoprolol and clonidine are taken at the same time, then when metoprolol is canceled, clonidine is canceled after a few days (due to the risk of withdrawal syndrome). Inducers of microsomal liver enzymes (rifampicin, barbiturates) lead to increased metabolism of metoprolol, to a decrease in the concentration of metoprolol in blood plasma and a decrease in the effect. Inhibitors (cimetidine, oral contraceptives, phenothiazines) increase the concentration of metoprolol in plasma. Allergens used for immunotherapy or allergen extracts for skin tests when used together with metoprolol increase the risk of systemic allergic reactions or anaphylaxis; iodine-containing radiopaque substances for iv administration increase the risk of anaphylactic reactions. Reduces xanthine clearance (except for diphillin), especially with initially increased theophylline clearance under the influence of smoking. It reduces the clearance of lidocaine, increases the concentration of lidocaine in blood plasma. Strengthens and prolongs the effect of antidepolarizing muscle relaxants; prolongs the anticoagulant effect of coumarins. When combined with ethanol, the risk of a pronounced decrease in blood pressure increases.

Dosage and administration

The tablets are taken orally with food or immediately after eating, without chewing and drinking with liquid. Arterial hypertension The initial daily dose is 50-100 mg in 1-2 doses (morning and evening). With insufficient therapeutic effect, the daily dose can be gradually increased to 100-200 mg and / or the additional appointment of other antihypertensive agents. The maximum daily dose of 200 mg. Angina pectoris, arrhythmias, prevention of migraine attacks - 100-200 mg / day in 2 divided doses (morning and evening). Secondary prevention of myocardial infarction - 200 mg / day 2 doses (morning and evening). Functional disorders of cardiac activity, accompanied by tachycardia - 100 mg / day in 2 divided doses (morning and evening). In elderly patients, with impaired renal function, as well as with the need for hemodialysis, the dose is not changed. In case of impaired liver function, the dose should be reduced depending on the clinical condition.

Overdose

Symptoms: severe severe sinus bradycardia, dizziness, nausea, vomiting, cyanosis, marked decrease in blood pressure, arrhythmia, ventricular ekstasystole, bronchospasm, fainting, in case of acute overdose - cardiogenic shock, loss of consciousness, coma, antrioventricular block and complete blockade ( cardiac arrest), cardialgia. The first signs of an overdose appear after 20 minutes - 2 hours after taking the drug. Treatment: gastric lavage and the appointment of adsorbing agents; symptomatic therapy: with a marked decrease in blood pressure, the patient should be in the Trendelenburg position; in the case of an excessive decrease in blood pressure, bradycardia and heart failure - in / in, with an interval of 2-5 minutes, beta-adrenostimulants - until the desired effect is achieved or in / in 0.5-2 mg of atropine sulfate. In the absence of a positive effect - dopamine, dobutamine or norepinephrine (norepinephrine). As a follow-up, it is possible to prescribe 1-10 mg of glucagon, staging a transvenous intracardial electrostimulator. With bronchospasm, beta2-adrenoreceptor stimulants should be administered iv. Metoprolol is poorly excreted by hemodialysis.

Special instructions

Monitoring of patients taking beta-blockers includes regular monitoring of heart rate and blood pressure, blood glucose in patients with diabetes mellitus. If necessary, for patients with diabetes mellitus, the dose of insulin or hypoglycemic agents prescribed by mouth should be selected individually. The patient should be trained in the method of calculating heart rate and instructed on the need for medical advice for heart rate less than 50 beats / min. When taking doses above 200 mg / day, cardioselectivity decreases. In heart failure, treatment with metoprolol begins only after reaching the stage of compensation. It is possible to increase the severity of hypersensitivity reactions (against the background of a burdened allergic history) and the lack of effect from the administration of usual doses of epinephrine (adrenaline). May aggravate symptoms of peripheral arterial circulatory disorders. Drug withdrawal is carried out gradually, reducing the dose within 10 days. With a sharp cessation of treatment, withdrawal syndrome may occur (increased angina attacks, increased blood pressure). Particular attention when discontinuing the drug must be given to patients with angina pectoris. With angina pectoris, the selected dose of the drug should provide a heart rate at rest within 55-60 beats / min, with a load of not more than 110 beats / min. Patients using contact lenses should take into account that, against the background of treatment with beta-blockers, a decrease in the production of tear fluid is possible. Metoprolol may mask some clinical manifestations of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, since it can increase symptoms. With diabetes, it can mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not increase insulin-induced glycemia and does not delay the restoration of blood glucose concentrations to normal levels. If necessary, the appointment of patients with bronchial asthma, beta2-adrenostimulants are used as concomitant therapy; with pheochromocytoma - alpha-blockers. If surgical intervention is necessary, it is necessary to warn the anesthetist about the therapy (the choice of a means for general anesthesia with minimal negative inotropic effect), drug withdrawal is not recommended. Drugs that reduce catecholamine stores (e.g., reserpine) can enhance the effect of beta-blockers, so patients taking these combinations of drugs should be constantly monitored by a doctor to detect an excessive decrease in blood pressure and bradycardia. In elderly patients, it is recommended to regularly monitor liver function. Correction of the dosage regimen is required only in the case of an elderly patient with increasing bradycardia (less than 50 beats / min), a marked decrease in blood pressure (systolic blood pressure below 100 mm Hg), AV blockade, bronchospasm, ventricular arrhythmias, severe liver dysfunction, sometimes it is necessary to stop treatment. Patients with severe renal failure are advised to monitor renal function. Special monitoring of the condition of patients with depressive disorders taking metoprolol should be carried out; in case of development of depression caused by taking beta-blockers, it is recommended to discontinue therapy. Due to the lack of sufficient clinical data, the drug is not recommended for use in children. Influence on the ability to drive vehicles and control mechanisms At the beginning of treatment with metoprolol, patients may experience dizziness, fatigue. In this case, they should refrain from driving vehicles and engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions. In the future, the determination of dose safety is carried out individually.