Bisoprolol

General characteristics. Structure:

Active ingredients: 2,5 mg, 5 mg or 10 mg of a bisoprolol of a fumarat.

Excipients: lactoses monohydrate, cellulose microcrystallic, silicon dioxide colloid, кросповидон, magnesium stearate.

Cover: [a gipromelloza, talc, titanium dioxide, a macrogoal 4000 (polyethyleneglycol 4000)] or [a cover film dry white, containing a gipromelloza, talc, titanium dioxide, a macrogoal 4000].

Pharmacological properties:

Pharmacodynamics. The selection beta1-adrenoblocker with insignificant sympathomimetic activity (SMA); has anti-hypertensive, antiarrhytmic and anti-anginal effect. Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions, renders negative hrono-, dromo-, batmo-and ionotropny action (urezhat heart rate, conductivity and excitability oppresses, reduces contractility of a myocardium). At increase in a dose has beta2-adrenoceptor blocking effect.

The General Peripheric Resistance of Vessels (GPRV) at the beginning of use of beta adrenoblockers in the first 24 h increases (as a result of reciprocal increase of activity of alpha adrenoceptors and elimination of stimulation of beta2-adrenoceptors), in 1-3 days is returned to initial, and at long appointment decreases.

Anti-hypertensive action is connected with reduction of the minute volume of blood circulation (MVBC), sympathetic stimulation of peripheral vessels, decrease of the activity the system renin-angiotensin-aldosteronovoy (SRAA) (has bigger value for patients with initial hypersecretion of a renin), recovery of sensitivity of baroreceptors of an aortic arch (there is no strengthening of their activity in response to a lowering of arterial pressure) and influence on the central nervous system. At arterial hypertension the effect occurs in 2-5 days, stable action – in 1-2 months.

Anti-anginal action is caused by reduction of need of a myocardium for oxygen as a result of an urezheniye of the heart rate (HR) and decrease in contractility, lengthening of a diastole, improvement of perfusion of a myocardium. Due to increase in end diastolic pressure in a left ventricle and increases in stretching of muscle fibers of ventricles can increase oxygen requirement, especially at patients with the chronic heart failure (CHF).

Antiarrhytmic action 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 AV a node) and on additional ways.

Unlike non-selective beta adrenoblockers at appointment in average therapeutic doses 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, does not cause a delay of ions of sodium in an organism.

At use in high doses renders the blocking effect on both subtypes of beta adrenoceptors.

Pharmacokinetics. Absorption. Bisoprolol almost completely (> 90%) is soaked up from digestive tract. Its bioavailability owing to an insignificant metabolization "at primary passing" through a liver (at about 10-15%) makes about 85-90% after intake. Meal does not influence bioavailability. Bisoprolol shows linear kinetics, and its concentration in a blood plasma are proportional to the accepted doses in the range of doses from 5 to 20 mg. The maximum concentration in a blood plasma is reached in 2-3 h.

Distribution. Bisoprolol is distributed quite widely. The volume of distribution makes 3,5 l/kg. Communication with proteins of a blood plasma reaches about 35%; capture by blood cells is not observed.

Metabolism. It is metabolized on an oxidizing way without the subsequent conjugation. All metabolites have strong polarity and are removed by kidneys. The main metabolites found in a blood plasma and urine do not show pharmacological activity. The data obtained as a result of experiments with microsomes of a liver of the person of in vitro show what бисопролол is metabolized first of all by means of CYP3A4 (about 95%), a CYP2D6 plays only a small role.

Removal. The clearance of a bisoprolol is defined by balance between its removal by kidneys in the form of not changed substance (about 50%) and oxidation in a liver (about 50%) to metabolites which then are also removed by kidneys. The general clearance makes  15,6±3,2 l/h, and the renal clearance is equal to 9,6±1,6 l/h. The elimination half-life makes 10-12 h.

Pharmacokinetics in special clinical cases. At patients with HSN concentration of a bisoprolol in a blood plasma is higher, and the elimination half-life increases to 17 h.

Indications to use:

Arterial hypertension, coronary heart disease (prevention of attacks of stable stenocardia).

Route of administration and doses:

Inside, in the morning on an empty stomach, without chewing, with a small amount of liquid. The dose of drug is selected individually, taking into account efficiency of treatment and ChSS.

At arterial hypertension and coronary heart disease (prevention of attacks of stable stenocardia) it is recommended to begin reception with 1 tablet of 5 mg of 1 times a day. In certain cases the initial dose can make 2,5 mg of 1 times a day. If necessary the dose is increased to 10 mg of 1 times a day. The maximum daily dose – 20 mg.

At patients with a renal failure (clearance of creatinine less than 20 ml/min.) or with the expressed abnormal liver functions the maximum daily dose – 10 mg.

Dose adjustment is not required from elderly patients. Duration of therapy is determined by the doctor.

Features of use:

Control of the patients accepting Bisoprolol has to include observation of ChSS and the ABP (in an initiation of treatment - daily, then 1 time in 3-4 months), the electrocardiogram, concentration of glucose in a blood plasma at patients with a diabetes mellitus (1 time in 4-5 months). At elderly patients it is recommended to monitor function of kidneys (1 times in 4-5 months).

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 beats/min.

Before an initiation of treatment it is recommended to conduct a research of function of external respiration at patients with the burdened bronchopulmonary anamnesis.

Approximately at 20% of patients with stenocardia beta adrenoblockers are inefficient. Main reasons: heavy coronary atherosclerosis with a low threshold of ischemia (ChSS less than 100 beats/min) and the increased final diastolic volume of a left ventricle (KDO LZh) breaking a subendocardial blood stream. At "smokers" efficiency of beta adrenoblockers is lower.

At a thyrotoxicosis бисопролол can mask certain clinical signs of a thyrotoxicosis (for example, tachycardia). Sharp cancellation is contraindicated as it is capable to strengthen symptomatology.

At a concomitant use of a clonidine its reception can be stopped only in several days after cancellation of a bisoprolol.

Strengthening of expressiveness of reaction of hypersensitivity and lack of effect of usual doses of Epinephrinum against the background of the burdened allergological anamnesis is possible.

In case of need performing planned surgical treatment carry out drug withdrawal in 48 hours prior to the beginning of the general anesthesia. If the patient accepted drug before operation, it should pick up medicine for the general anesthesia with the minimum negative ionotropny effect.

Reciprocal activation of a vagus nerve can be eliminated with intravenous administration of atropine (1-2 mg).

The medicines 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 detection of arterial hypotension or bradycardia.

In case of emergence in patients of advanced age of the accruing bradycardia (   less than 50 beats/min), arterial hypotension (the GARDEN is lower than 100 mm hg), an atrioventricular block, 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 development of the depression caused by reception of beta adrenoblockers.

It is impossible to interrupt sharply treatment because of danger of development of heavy arrhythmias and a myocardial infarction. Cancellation is carried out gradually, reducing a dose within 2 weeks and more (lower a dose by 25% in 3-4 days).

Drug should be cancelled before a research of content in blood and urine of catecholamines, a normetanefrin and vanililmindalny acid, credits of antinuclear antibodies.

The patients using contact lenses have to consider that against the background of use of beta adrenoblockers reduction of products of the lacrimal liquid is possible.

At use for patients with a pheochromocytoma there is a risk of development of paradoxical arterial hypertension (if it is previously not reached effective alpha адреноблокада).

At a diabetes mellitus бисопролол 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 a blood plasma to normal level does not detain.

Patients with bronkhospastichesky diseases can appoint cardioselective adrenoblockers in case of intolerance and/or inefficiency of other hypotensive medicines, but at the same time it is necessary to watch a dosage strictly. The overdose is dangerous by development of a bronchospasm.

Influence on ability of control of vehicles and mechanisms. 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.

Use at pregnancy and during breastfeeding. Bisoprolol at pregnancy is not recommended to apply and during feeding by a breast as he can make harmful effects on the course of pregnancy and/or on a fruit (beta adrenoblockers reduce placental perfusion that leads to delay of growth of a fruit, pre-natal death of a fruit, an abortion or premature births) or the newborn. If Bisoprolol is in exceptional cases applied during pregnancy, then treatment has to be stopped by him in 72 hours prior to the expected term of childbirth because of a possibility of development of bradycardia, a hypoglycemia and respiratory depression on the newborn. If it is impossible, then after delivery the newborn has to be under careful medical observation. Symptoms of a hypoglycemia can usually be expected within the first three days.

Drug is not recommended to be used in the period of a lactation. In need of drug use Bisoprolol in the period of a lactation breastfeeding needs to be stopped.

Side effects:

Frequency: very often (more or equally 1/10); often (more than 1/100, less than 1/10); infrequently (more than 1/1000, less than 1/100); seldom (more than 1/10000, less than 1/1000); very seldom (less than 1/10000, including separate messages).

From the central nervous system: often - increased fatigue, an adynamy, dizziness, a headache; infrequently - drowsiness or sleeplessness, a depression; seldom - hallucinations, "dreadful" dreams, spasms, confusion of consciousness or short-term loss of memory.

From sense bodys: seldom - a vision disorder, reduction of secretion of the lacrimal liquid, dryness and morbidity of eyes, a hearing disorder; very seldom – conjunctivitis; taste change.

From cardiovascular system: very often - a sinus bradycardia; often – the expressed decrease in the ABP, manifestation of a vasomotor spasm (strengthening of disturbance of peripheric circulation, a cold snap of the lower extremities, paresthesias), aggravation of symptoms of a course of chronic heart failure with development of peripheral hypostases; infrequently - disturbance of AV of conductivity, orthostatic hypotension; very seldom – a stethalgia.

From the alimentary system: often - dryness of a mucous membrane of an oral cavity, nausea, vomiting, diarrhea, a lock; seldom - hepatitis.

From respiratory system: infrequently – a bronchospasm at patients with bronchial asthma or a chronic obstructive pulmonary disease in the anamnesis; seldom – allergic rhinitis.

From endocrine system: seldom - a hyperglycemia (patients with a diabetes mellitus have 2 types), a hypoglycemia (at patients with a diabetes mellitus of 1 type).

Allergic reactions: seldom – a skin itch, skin rash, a small tortoiseshell.

From integuments: seldom - sweating strengthening, a dermahemia; very seldom - psoriazopodobny skin reactions, an aggravation of symptoms of a course of psoriasis, an alopecia.

From a musculoskeletal system: infrequently - muscular weakness, spasms in gastrocnemius muscles, an arthralgia.

Laboratory indicators: seldom - increase in activity of "hepatic" transaminases, a gipertriglitseridemiya; in some cases - thrombocytopenia, a leukopenia, an agranulocytosis, increase in concentration of bilirubin.

Influence on a fruit: pre-natal growth inhibition, hypoglycemia, bradycardia.

Others: disturbance of a potentiality, syndrome of "cancellation" (strengthening of attacks of stenocardia, increase in the ABP).

Interaction with other medicines:

The allergens used for an immunotherapy or extracts of allergens for skin tests increase risk of emergence of heavy system allergic reactions or an anaphylaxis at the patients receiving бисопролол.

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

Antiarrhytmic means of the I class (for example, quinidine, Disopyramidum, lidocaine, Phenytoinum, флекаинид, пропафенон) at simultaneous use with bisoprololy can strengthen negative inotropic effect and extend AV carrying out (it is required careful clinical and electrocardiographic observations).

Blockers of "slow" calcium channels (BMKK) like verapamil and, to a lesser extent, diltiazem at simultaneous use with bisoprololy can lead to decrease in sokratitelny ability of a myocardium and disturbance of AV of conductivity. Intravenous administration of verapamil / дилтиазема is not recommended to the patients accepting beta adrenoblockers as it can lead to the blockade expressed to arterial hypotension and AV.

Antiaritmicheksy means of the III class (for example, Amiodaronum) can strengthen disturbance of AV of conductivity.

Cardiac glycosides, Methyldopum, Reserpinum and гуанфацин increase risk of development or aggravation of bradycardia, AV of blockade, a cardiac standstill and heart failure.

Blockers of "slow" calcium channels of derivatives of dihydropyridine (for example, nifedipine, фелодипин, амлодипин) at simultaneous use with bisoprololy can increase risk of development of arterial hypotension, deterioration in sokratitelny function of heart.

Diuretics, clonidine, sympatholytics, гидралазин and other antihypertensives can lead to excessive decrease in the ABP.

Anti-hypertensive effect non-steroidal anti-inflammatory drugs (a delay of sodium and blockade of synthesis of prostaglandins kidneys) weaken, glucocorticosteroids and estrogen (a sodium delay).

Effect of beta adrenoblockers for topical administration (for example, eye drops for treatment of glaucoma) can strengthen system effects of a bisoprolol (decrease in the ABP, urezheny ChSS).

Parasympathomimetics at simultaneous use with bisoprololy can strengthen disturbance of AV of conductivity and increase risk of development of bradycardia.

Bisoprolol with beta-adrenergic agonists (for example, изопреналин, Dobutaminum) can lead simultaneous use of drug to decrease in effect of both drugs. The combination of a bisoprolol to the adrenomimetika influencing on beta and alpha adrenoceptors (for example, Norepinephrinum, Epinephrinum), can strengthen the vasopressor effects of these means arising with participation of alpha adrenoceptors, leading to increase in the ABP. Similar interactions are more probable at use of non-selective beta adrenoblockers.

Meflokhin at simultaneous use with bisoprololy can increase risk of development of bradycardia.

Phenytoinum at in introduction, means for inhalation general anesthesia (derivatives of hydrocarbons) increase expressiveness of cardiodepressive action and probability of decrease in the ABP.

Strengthens hypoglycemic effect of insulin and hypoglycemic means for intake, masks symptoms of the developing hypoglycemia (tachycardia, increase in the ABP).

At simultaneous use with floktafeniny can suppress compensatory cardiovascular reactions that promotes development of the expressed arterial hypotension or shock owing to strengthening of action of a floktafenin.

At simultaneous use of drug and inhibitors of cholinesterase (including такрин) delay of atrioventricular conductivity and/or strengthening of bradycardia is possible.

At simultaneous use of drug and Baclofenum strengthening of anti-hypertensive action of a bisoprolol is possible.

At simultaneous use of drug and an amifostin strengthening of anti-hypertensive action of a bisoprolol is possible.

At combined use of drug and a sultoprid increase in risk of development of ventricular arrhythmia is possible.

Extends action of not depolarizing muscle relaxants and anticoagulating effect of coumarins.

Rub - and tetracyclic antidepressants, antipsychotic means (neuroleptics), ethanol, sedative and hypnagogues strengthen oppression of the central nervous system.

Simultaneous use with MAO inhibitors owing to considerable strengthening of anti-hypertensive action is not recommended, having rummaged in treatment between reception of MAO inhibitors and a bisoprolola has to make not less than 14 days.

Not hydrogenated alkaloids of an ergot increase risk of development of disturbances of peripheric circulation.

Ergotamine increases risk of development of disturbance of peripheric circulation; Sulfasalazinum increases concentration of a bisoprolol in a blood plasma; rifampicin shortens an elimination half-life.

Contraindications:

- hypersensitivity to a bisoprolol, other components of drug and other beta adrenoblockers;
- the acute and chronic heart failure in a decompensation stage demanding performing inotropic therapy;
- cardiogenic shock;
- AV blockade of the II-III degree (without artificial pacemaker);
- sinuatrial blockade;
- sick sinus syndrome;
- heavy bradycardia (ChSS <50 уд/мин);
- a cardiomegaly (without symptoms of heart failure);
- heavy arterial hypotension (systolic arterial pressure (SAP) < 90 мм рт.ст.);
- severe forms of bronchial asthma and chronic obstructive pulmonary disease;
- heavy disturbances of peripheric circulation and/or Reynaud's syndrome;
- a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
- lactation period;
- a concomitant use of monoamine oxidase inhibitors (MAO) (except for MAO inhibitors of V type);
- the accompanying use of a floktafenin and sultoprid;
- lactose intolerance, insufficiency of lactase or syndrome of glyukozo-galaktozny malabsorption;
- metabolic acidosis;
- simultaneous intravenous administration of verapamil or diltiazem;
- age up to 18 years.

With care:
- liver failure;
- heavy renal failure (clearance of creatinine less than 20 ml/min.);
- Printsmetal's stenocardia;
- myasthenia;
- thyrotoxicosis;
- diabetes mellitus;
- atrioventikulyarny blockade of the I degree;
- a depression (including in the anamnesis);
- psoriasis;
- advanced age;
- the burdened allergological anamnesis;
- at observance of a rigid diet (an exception of food of proteins of animal origin).

Overdose:

Symptoms: arrhythmia, ventricular premature ventricular contraction, the expressed bradycardia, an atrioventricular block, an acute heart failure, a hypoglycemia, the expressed lowering of arterial pressure, a Crocq's disease, the complicated breath, a bronchospasm, dizziness, unconscious states, spasms.

Treatment: a gastric lavage and purpose of the adsorbing medicines; symptomatic therapy; at development of bradycardia - intravenous administration (in/in) 1-2 mg of atropine or statement, if necessary, an artificial pacemaker; at an atrioventricular block - beta-adrenergic agonists, such as Epinephrinum, or statement, if necessary, an artificial pacemaker; at ventricular premature ventricular contraction – lidocaine (drugs 1A of a class are not used); at a lowering of arterial pressure the patient has to be in the provision of Trendelenburga; if there are no fluid lungs signs – in/in administration of plasma substituting solutions, at inefficiency – introduction of Epinephrinum, dopamine, Dobutaminum (for maintenance of chronotropic and ionotropny action and elimination of the expressed decrease in the ABP); at an acute heart failure – cardiac glycosides, diuretics; at a hypoglycemia – in/in introduction of a dextrose (glucose); at spasms – intravenously diazepam; at a bronchospasm – beta2-adrenomimetik and/or Aminophyllinum it is inhalation.

Storage conditions:

In the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 2,5 mg, 5 mg and 10 mg. On 10, 15 or 30 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. 1, 2, 3, 5 or 6 blister strip packagings on 10 tablets, or 1, 2 or 4 blister strip packagings on 15 tablets, or 1 or 2 blister strip packagings on 30 tablets together with the application instruction in a pack from a cardboard.