Absorption: When taken orally, metoprolol is almost completely absorbed (approximately 95%) from the gastrointestinal tract. The plasma concentration of metoprolol is linearly dependent on the dose within therapeutic ranges.

Peak plasma concentration is achieved within 1.5-2 hours after oral administration.

Metabolism: Metoprolol undergoes intense presystemic metabolism. After oral administration of the first dose, about 50% of the dose reaches the systemic circulation. With repeated doses, systemic bioavailability increases to about 70%. Concurrent food intake increases bioavailability by 20-40%.

Distribution: Metoprolol has low plasma protein binding, approximately 5-10%. The volume of distribution is 5.6 L/kg. It crosses the blood-brain barrier and placental barrier. Metoprolol is excreted in breast milk in insignificant amounts.

Metabolism: Metoprolol undergoes oxidative metabolism in the liver, primarily involving the CYP2D6 isoenzyme, forming three main metabolites, none of which have clinically significant β-blocking effects.

Excretion: The average half-life of metoprolol in plasma is about 3.5 hours (ranging from 1 to 9 hours in patients with "slow" metabolism). Plasma clearance is approximately 1 L/min.

Metoprolol is predominantly eliminated by the kidneys (about 95%). Approximately 5% of the administered dose is excreted unchanged by the kidneys, with this percentage occasionally reaching 30%. Metoprolol is not removed by hemodialysis.

Pharmacokinetics in Special Patient Populations: Elderly patients show no significant changes in metoprolol pharmacokinetics compared to younger patients.

Systemic bioavailability and elimination of metoprolol remain unchanged in patients with impaired kidney function. However, metabolite elimination is reduced in these patients. Significant metabolite accumulation has been observed in patients with glomerular filtration rates less than 5 mL/min. However, such metabolite accumulation does not intensify the β-adrenoblocking effect.

In patients with impaired liver function, metoprolol pharmacokinetics change slightly due to low plasma protein binding. However, in patients with severe liver cirrhosis or portacaval anastomosis, metoprolol bioavailability may increase, and total clearance may decrease to 0.3 mL/min.

In patients with portacaval anastomosis, total clearance was approximately 300 mL/min, and the area under the concentration-time curve (AUC) was six times higher compared to healthy patients.

After oral administration, metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract, with the maximum plasma concentration of the active substance reached within 1-2 hours. Following absorption, metoprolol undergoes significant first-pass metabolism in the liver. Plasma protein binding is low, approximately 5-10%. The volume of distribution (Vd) is 5.6 L/kg. Metoprolol quickly distributes into tissues, crosses the blood-brain barrier, and the placental barrier. It is excreted in breast milk. Metoprolol undergoes oxidative metabolism in the liver, primarily involving the CYP2D6 isoenzyme, forming three major metabolites, none of which have clinically significant beta-adrenoblocking effects. The half-life (T1/2) of metoprolol in plasma is 3-4 hours and remains unchanged during the course of treatment. More than 95% of the administered dose is eliminated by the kidneys, with approximately 5% of the dose excreted unchanged by the kidneys.

 

• Increased sensitivity to metoprolol or to other components of the drug or to other beta-adrenergic blockers;

• Atrioventricular block of II and III degree (without artificial pacemaker);

• Decompensated heart failure;

• Patients receiving long-term or intermittent therapy with inotropic agents and agents acting on beta-adrenoceptors;

• Clinically significant sinus bradycardia;

• Sinus node weakness syndrome;

• Cardiogenic shock;

• Severe peripheral circulation disorders, including gangrene threat;

• Arterial hypotension (systolic blood pressure less than 90 mmHg);

• Patients with acute myocardial infarction with heart rate less than 45 beats per minute, PQ interval duration more than 0.24 seconds, or systolic blood pressure less than 100 mmHg;

• Intravenous administration of "slow" calcium channel blockers (CCBs) like verapamil and diltiazem is contraindicated in patients receiving beta-blockers (see section "Interaction with other medicinal products");

• Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome;

• Age under 18 years (efficacy and safety not established);

• Severe forms of bronchial asthma and chronic obstructive pulmonary disease (COPD);

• Concomitant use of monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products");

• Pheochromocytoma (without concomitant use of alpha-adrenergic blockers);

• Breastfeeding period.

With caution:

• First-degree atrioventricular (AV) block;

• Prinzmetal angina;

• Diabetes mellitus;

• Severe liver dysfunction;

• Severe renal impairment (creatinine clearance (CrCl) less than 40 mL/min);

• COPD (lung emphysema, chronic obstructive bronchitis);

• Bronchial asthma;

• Pheochromocytoma (with concomitant use of alpha-adrenergic blockers);

• Pregnancy;

• Psoriasis;

• Thyrotoxicosis;

• Allergic reactions in history (possible increase in sensitivity to allergens, exacerbation of arterial hypertension, and reduced therapeutic response to epinephrine (adrenaline));

• Elderly age;

• Depression (including in history);

• Peripheral vascular occlusive diseases (intermittent claudication, Raynaud's syndrome);

• Metabolic acidosis.

According to the World Health Organization, adverse effects are classified according to their frequency of occurrence as follows: very common (10% of administrations); common (1% and <10%); uncommon (0.1% and <1%); rare (0.01% and <0.1%); very rare (<0.01%); frequency unknown (insufficient data to assess frequency of occurrence).

Hematologic Disorders: very rare - thrombocytopenia, leukopenia.

Cardiovascular System: common - sinus bradycardia, postural disturbances (very rarely leading to fainting), extremity coldness, palpitations; uncommon - temporary exacerbation of heart failure symptoms, first-degree AV block; cardiogenic shock in patients with acute myocardial infarction, peripheral edema, chest pain; rare - other myocardial conduction disorders, arrhythmias; very rare - gangrene in patients with pre-existing severe peripheral circulation disorders.

Nervous System: very common - increased fatigue; common - headache, dizziness; uncommon - paresthesia, seizures, depression, decreased attention span, drowsiness or insomnia, nightmares; rare - increased nervousness, anxiety; very rare - amnesia/memory impairment, apathy, hallucinations.

Sense Organs: rare - vision disorders, dryness and/or irritation of the eyes, conjunctivitis; very rare - ringing in the ears, taste disturbances.

Digestive System: common - nausea, abdominal pain, diarrhea, constipation; uncommon - vomiting; rare - dryness of the oral mucosa.

Liver: rare - liver function disorders, elevation of "liver" transaminase activity; very rare - hepatitis.

Skin: uncommon - skin rash (psoriasis-like, urticaria), increased sweating; rare - hair loss (alopecia); very rare - photosensitivity, exacerbation of psoriasis; frequency unknown - skin itching, redness of the skin, angioedema (Quincke's edema).

Respiratory System: common - dyspnea on exertion; uncommon - bronchospasm; rare - rhinitis.

Endocrine System: rare - hypo-, hyperglycemia in patients with type 1 diabetes, masking of symptoms of thyrotoxicosis.

Musculoskeletal System: very rare - arthralgia; frequency unknown - chest pain.

Metabolism: uncommon - weight gain; rare - exacerbation of latent diabetes.

Other: rare - impotence/sexual dysfunction, Peyronie's disease.

Laboratory Parameters: very rare - decrease in high-density lipoprotein cholesterol concentration and increase in plasma triglyceride concentration.

Overdose:

Toxicity

Metoprolol at a dose of 7.5 grams in adults caused intoxication with a fatal outcome. A 5-year-old child who ingested 100 mg of metoprolol, after gastric lavage, did not show signs of intoxication. Administration of 450 mg of metoprolol to a 12-year-old adolescent resulted in moderate intoxication. Administration of 1.4 grams and 2.5 grams of metoprolol in adults caused moderate and severe intoxication, respectively.

Symptoms

In cases of overdose with the drug, the most serious symptoms are from the cardiovascular system, however, sometimes, especially in children and adolescents, symptoms from the central nervous system and lung function suppression may prevail, including bradycardia, second- or third-degree AV block, asystole, severe hypotension, weak peripheral perfusion, heart failure, cardiogenic shock, respiratory depression, apnea, as well as increased fatigue, altered consciousness, loss of consciousness, tremor, seizures, increased sweating, paresthesia, bronchospasm, nausea, vomiting, esophageal spasm, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia, renal dysfunction, transient myasthenic syndrome.

Concomitant intake of ethanol, hypotensive drugs, quinine, or barbiturates may worsen the patient's condition.

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

Treatment

Administration of activated charcoal, if necessary - gastric lavage.

Atropine (intravenously at a dose of 0.25-0.5 mg for adults, 10-20 mcg/kg body weight for children) should be administered before gastric lavage (risk of vagus nerve stimulation).

If necessary, ensure airway patency (intubation) and adequate lung ventilation, replenish circulating blood volume (CBV), infuse 5% glucose solution, monitor ECG, administer intravenous atropine 1.0-2.0 mg (repeat administration if necessary, especially in case of vagal symptoms).

In case of severe hypotension, intravenous administration of a selective beta1-agonist (e.g., dobutamine) with an interval of 2-5 minutes or infusion until achieving the therapeutic effect is indicated. In the absence of a selective beta1-agonist, intravenous administration of dopamine or atropine sulfate for vagal blockade is possible. Glucagon can also be administered intravenously at a dose of 50-150 mcg/kg body weight at 1-minute intervals (positive inotropic and chronotropic effect on the myocardium). If the therapeutic effect is not achieved, other sympathomimetics such as norepinephrine (noradrenaline) can be used. In some cases, adding epinephrine (adrenaline) to the therapy may be effective.

For bronchospasm relief, a beta2-agonist (e.g., terbutaline intravenously) should be used. For seizures, slow intravenous administration of diazepam is recommended. It should be noted that the doses of antidotes required to alleviate symptoms of beta-blocker overdose are much higher than therapeutic doses because beta-adrenoceptors are bound by beta-blockers.

Metoprolol is poorly removed by hemodialysis.

Metoprolol should be taken orally, on an empty stomach, during or immediately after a meal.

Tablets can be divided in half (but not chewed) and taken with liquid.

Arterial hypertension:

100-200 mg of Metoprolol once daily in the morning or in two divided doses: in the morning and evening. If necessary, the dose can be increased or another antihypertensive agent can be added.

Long-term antihypertensive therapy with 100-200 mg of Metoprolol per day helps to reduce overall mortality, including sudden death, as well as the frequency of stroke and coronary circulation disorders in patients with arterial hypertension.

Angina:

100-200 mg per day in two divided doses; morning and evening. If necessary, another antianginal agent may be added to the therapy.

Cardiac rhythm disturbances, including supraventricular tachycardia:

100-200 mg per day in two divided doses (morning and evening). If necessary, another antiarrhythmic agent may be added to the therapy.

In complex therapy after myocardial infarction:

The maintenance dose is 200 mg per day in two divided doses (morning and evening). Administration of Metoprolol at a dose of 200 mg per day reduces mortality in patients who have had a myocardial infarction and reduces the risk of recurrent myocardial infarction (including in patients with diabetes mellitus).

Functional cardiac disorders accompanied by tachycardia:

100 mg of Metoprolol once daily, it is recommended to take the tablet in the morning. If necessary, the dose may be increased.

Migraine prophylaxis:

100-200 mg per day in two divided doses; morning and evening.

Hyperthyroidism:

150-200 mg per day in 3-4 doses.

Use in special patient groups:

Use in patients with renal insufficiency:

No dose adjustment is required in case of renal impairment.

Use in patients with hepatic impairment:

Given the low degree of plasma protein binding of metoprolol, dose adjustment is not required. However, in severe liver dysfunction (in patients with severe liver cirrhosis or portacaval anastomosis), a reduction in the dose of Metoprolol may be necessary.

Use in elderly patients:

Elderly patients are recommended to start treatment with 50 mg (1/2 tablet of 100 mg) per day (since sudden blood pressure reduction or increasing bradycardia may be more pronounced).

Actions in case of discontinuation of the drug:

If it becomes necessary to interrupt or discontinue treatment with Metoprolol after prolonged therapy, the dosage of the drug should be gradually reduced by half over a minimum of 2 weeks.

In case of the appearance of withdrawal syndrome, dose reduction should occur more slowly. Abrupt cessation of the drug intake may cause myocardial ischemia and may exacerbate angina or myocardial infarction, as well as exacerbate arterial hypertension.