Bisoprolol, 10 mg 30 pcs.

A selective beta1-adrenoblocker, without its own sympathomimetic activity, has no membrane stabilizing effect. It reduces plasma renin activity, decreases myocardial oxygen demand, reduces HR (at rest and under load).

It has hypotensive, antiarrhythmic and antianginal action. By blocking in low doses beta1-adrenoreceptors in heart, it decreases catecholamine-stimulated cAMP formation from ATP, decreases intracellular calcium ions flow, produces negative chrono-, dromo-, batmo- and inotropic effects, inhibits myocardial conduction and excitability and decreases AV-conduction.

If the dose is increased above the therapeutic, it has a beta2-adrenoblocking effect.

The HRP at the beginning of drug administration, in the first 24 h, increases (as a result of reciprocal increase of alpha-adrenoreceptor activity and elimination of beta2-adrenoreceptor stimulation) which returns to baseline in 1-3 days, and decreases with prolonged administration.

Hypotensive effect is associated with decreased minute blood volume, sympathetic stimulation of peripheral vessels, decreased activity of renin-angiotensin system (of great importance for patients with initial renin hypersecretion), restoration of sensitivity in response to BP decrease and influence on CNS. For arterial hypertension the effect comes in 2-5 days, stable effect – in 1-2 months.

The antianginal effect is caused by decrease of myocardial oxygen demand as a result of decrease of HR and contractility, prolongation of diastole, improvement of myocardial perfusion. By increasing left ventricular end-diastolic pressure and increasing ventricular muscle fiber stretch may increase oxygen demand, especially in patients with chronic heart failure.

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), reduction of the rate of spontaneous excitation of sinus and ectopic pacemakers and slowing of AV conduction (mainly in the antegrade and, to a lesser degree, in the retrograde direction through the AV node) and through additional pathways.

In contrast to non-selective beta-adrenoblockers, when administered in medium therapeutic doses, 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, does not cause delay of sodium ions (Na+) in the body; the severity of atherogenic action does not differ from that of propranolol.

Pharmacokinetics

Intake and distribution

Absorption is 80-90%; absorption is not affected by food intake. Cmax in blood plasma is observed after 1-3 hours.

The binding to plasma proteins is about 30%. It passes through the BBB and placental barrier to a small extent, in small amounts is excreted with breast milk.

Metabolism and excretion

50% of the dose is metabolized in the liver with the formation of inactive metabolites.

The T1/2 is 10-12 hours. About 98% is excreted in the urine – 50% unchanged, less than 2% in the bile.

Indications

– arterial hypertension;

– CHD: prevention of angina attacks.

Active ingredient

Composition

Bisoprolol fumarate 10 mg.

Supplementary substances:

croscarmellose sodium (primellose),

povidone (polyvinylpyrrolidone medium molecular weight),

Pregelatinized starch (starch 1500),

silica colloidal dioxide (aerosil),

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microcrystalline cellulose,

lactose (milk sugar),

magnesium stearate.

Composition of the film coating:

Opadray II (polyvinyl alcohol, partially hydrolyzed, titanium dioxide, talc, macrogol (polyethylene glycol 3350), iron oxide (II) dye).

How to take, the dosage

The drug is taken orally in the morning, on an empty stomach, without chewing, in an initial dose of 5 mg once a day. If necessary, the dose is increased to 10 mg once daily. Maximal daily dose is 20 mg/day.

In patients with impaired renal function at a CKR of less than 20 ml/min or with significant hepatic impairment, the maximum daily dose should be 10 mg.

Dose adjustment in elderly patients is not required.

Interaction

Allergens used for immunotherapy or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving bisoprolol.

Iodine-containing X-ray contrast agents for IV administration increase the risk of anaphylactic reactions.

Phenytoin when administered by IV, drugs for inhaled general anesthesia (hydrocarbon derivatives) increase the severity of cardiodepressive effects and the likelihood of BP reduction.

Alter the effectiveness of insulin and oral hypoglycemic drugs, mask the symptoms of developing hypoglycemia (tachycardia, increased BP).

Decreases clearance of lidocaine and xanthines (except diphylline) and increases their plasma concentrations, especially in patients with initially increased clearance of theophylline under the influence of smoking.

The hypotensive effect is weakened by NSAIDs (Na+ retention and blockade of prostaglandin synthesis by the kidneys), GCS and estrogens (Na+ ion retention).

The cardiac glycosides, methyldopa, reserpine and guanfacine, slow calcium channel blockers (verapamil, diltiazem), amiodorone and other antiarrhythmic drugs increase the risk of developing or worsening bradycardia, AV blockade, heart failure and heart failure.

Nifedipine may cause a significant decrease in BP.

Diuretics, clonidine, sympatholytics, hydralazine, and other hypotensive drugs may cause excessive BP lowering.

Longens the effects of nondepolarizing myorelaxants and the anticoagulant effect of coumarins.

Tri- and tetracyclic antidepressants, antipsychotic drugs (neuroleptics), ethanol, sedatives and sleeping pills increase CNS depression.

The concomitant use with MAO inhibitors is not recommended due to the significant increase in hypotensive effect; a break in treatment between MAO inhibitors and bisoprolol should be at least 14 days.

Unhydrogenated ergot alkaloids increase the risk of peripheral circulatory disorders.

Ergotamine increases the risk of peripheral circulatory disorders; sulfasalazine increases the plasma concentration of bisoprolol; and rifampicin shortens the elimination half-life.

Special Instructions

Control of patients taking Bisoprolol should include measurement of HR and BP (at the beginning of treatment – daily, then – once every 3-4 months), ECG, determination of blood glucose level in diabetic patients (once every 4-5 months). In elderly patients it is recommended to monitor kidney function (once every 4-5 months).

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.

We recommend an external respiratory function study in patients with a history of poor bronchopulmonary function before starting treatment.

In about 20% of patients with angina pectoris, beta-adrenoblockers are ineffective. The main causes are severe coronary atherosclerosis with a low ischemic threshold (heart rate less than 100 bpm) and increased left ventricular end-diastolic volume, which impairs subendocardial blood flow.

The effectiveness of beta-adrenoblockers is lower in smoking patients.

Patients who wear contact lenses should be aware that the treatment may decrease tear fluid production.

When used in patients with pheochromocytoma, there is a risk of paradoxical arterial hypertension (unless effective alpha-adrenoblockade has first been achieved).

In thyrotoxicosis, Bisoprolol may mask certain clinical signs of thyrotoxicosis, such as tachycardia. Abrupt withdrawal in patients with thyrotoxicosis is contraindicated because it can exacerbate the symptoms.

In diabetes mellitus, it 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.

If clonidine is taken concomitantly, its administration may be discontinued only after several days of Bisoprolol withdrawal.

The severity of hypersensitivity reactions and lack of effect of usual doses of zpinephrine against a background of a strong allergic history may increase. If planned surgical treatment is necessary, the drug should be withdrawn 48 hours before the start of general anesthesia. If the patient has taken the drug before the surgery, he should choose the drug for general anesthesia with minimal negative inotropic effect.

The reciprocal activation of the vagus nerve can be eliminated by IV administration of atropine (1-2 mg).

Drugs that reduce catecholamine stores (including reserpine) can potentiate the effects of beta-adrenoblockers, so patients taking these combinations of drugs should be kept under constant medical observation for signs of marked lowering of BP or bradycardia.

Patients with bronchospastic disorders may be prescribed cardioselective adrenoblockers if other hypotensive medications are intolerant and/or ineffective. Overdose is dangerous with the development of bronchospasm.

If elderly patients show increasing bradycardia (less than 50 bpm), marked BP lowering (systolic BP below 100 mmHg), AV-blockade, the dose should be reduced or the treatment should be stopped.

It is recommended to discontinue therapy if depression develops.

The treatment should not be stopped abruptly because of the risk of severe arrhythmias and myocardial infarction. Withdrawal is done gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% every 3 to 4 days). It should be discontinued before testing the blood and urine content of catecholamines, normetanephrine and vanillinmindalic acid, and antinuclear antibody titers.

Impact on driving and operating machinery

At the time of treatment, care must be taken when driving motor vehicles and engaging in other potentially dangerous activities that require increased concentration and quick psychomotor reactions.

Contraindications

– shock (including. cardiogenic);

– collapse;

– pulmonary edema;

– acute heart failure;

– Chronic heart failure in decompensation stage;

– AV blockade of II and III degree;

– sinoatrial block;

– SSRI;

– marked bradycardia;

– Prinzmetal angina;

– cardiomegaly (without signs of heart failure);

– arterial hypotension (systolic BP less than 100 mm Hg.systolic BP less than 100 mm Hg, especially in myocardial infarction);

– a history of severe bronchial asthma and chronic obstructive pulmonary disease;

– concomitant use of MAO inhibitors (except MAO-B);

– advanced peripheral circulatory disorders, Raynaud’s disease;

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– pheochromocytoma (without concomitant use of alpha-adrenoblockers);

– metabolic acidosis;

– under 18 years of age (efficacy and safety have not been established);

– hypersensitivity to the components of the drug and other beta-adrenoblockers.

With caution, the drug should be used in patients with hepatic insufficiency, chronic renal insufficiency, myasthenia gravis, thyrotoxicosis, diabetes, 1st degree AV blockade, depression (including in anamnesis), psoriasis, and elderly patients.

Side effects

CNS disorders: increased fatigue, weakness, dizziness, headache, sleep disorders, depression, anxiety, confusion or short-term memory loss, hallucinations, asthenia, myasthenia gravis, paresthesias in extremities (in patients with intermittent claudication and Raynaud’s syndrome), tremor.

Sense organs: visual impairment, decreased tear fluid secretion, dry and painful eyes, conjunctivitis.

Cardiovascular system disorders: sinus bradycardia, palpitations, myocardial conduction disorders, AV -blockade (up to the development of complete transverse blockade and cardiac arrest), arrhythmias, weakened myocardial contractility, development (aggravation) of chronic heart failure (swelling of ankles, feet, dyspnea), BP decrease, orthostatic hypotension, manifestation of angiospasm (intensification of peripheral circulatory disorders, coldness of the lower extremities, Raynaud’s syndrome), chest pain.

Digestive system disorders: dry mouth, nausea, vomiting, abdominal pain, constipation or diarrhea, liver disorders (dark urine, jaundice of sclerae or skin, cholestasis), changes in taste.

Respiratory system: nasal congestion, difficulty in breathing when prescribed in high doses (loss of selectivity) and/or in susceptible patients – laryngo- and bronchospasm.

Endocrine system: hyperglycemia (in patients with insulin-dependent diabetes), hypoglycemia (in patients receiving insulin), hypothyroidism.

Allergic reactions: skin itching, rash, urticaria.

Dermatological reactions: increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions, exacerbation of psoriasis symptoms.

Laboratory findings: thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia, changes in liver enzymes activity (increased ALT, ACT), bilirubin levels, triglycerides.

Fetal effects: intrauterine growth retardation, hypoglycemia, bradycardia.

Others: back pain, arthralgia, decreased libido, decreased potency, withdrawal syndrome (increased angina attacks, increased BP).

Overdose

Symptoms: arrhythmia, ventricular extrasystole, marked bradycardia, AV-blockade, marked BP decrease, chronic heart failure, cyanosis of finger nails or palms, difficulty breathing, bronchospasm, dizziness, fainting, seizures.

Treatment: gastric lavage and administration of adsorbents; symptomatic therapy: in developed AV blockade – IV injection of 1-2 mg of atropine, epinephrine, or placement of a temporary pacemaker; in ventricular extrasystole – lidocaine (Class IA drugs are not used ); if BP decreases – the patient should be in Trendelenburg position; If there are no signs of pulmonary edema – IV plasma exchange solutions, if ineffective – injection of epinephrine, dopamine, dobutamine (to maintain chronotropic and inotropic action and to eliminate marked BP decrease); in heart failure – cardiac glycosides, diuretics, glucagon; in convulsions – IV diazepam; in bronchospasm beta-adreno stimulants inhaled.

Similarities