Atrovent Beta

Prevention and symptomatic treatment of obstructive airway diseases with reversible airway obstruction, such as:

bronchial asthma,

chronic obstructive pulmonary disease,

chronic obstructive bronchitis with or without emphysema.

Symptomatic treatment of chronic obstructive airway diseases with reversible airway obstruction, such as:

bronchial asthma,

chronic obstructive pulmonary disease,

chronic obstructive bronchitis with or without emphysema.

The dose should be selected individually. In the absence of other recommendations of the doctor, the use of the following doses is recommended.

Adults and children over 6 years old

Treatment of seizures. In most cases, two inhalation doses of aerosol are sufficient to relieve symptoms. If there is no relief of breathing within 5 minutes, you can use an additional 2 inhalation doses.

If the effect is absent after four inhalation doses and additional inhalations are required, you should immediately seek medical attention.

Intermittent and long-term therapy. 1-2 inhalations at a time, up to 8 inhalations per day (on average, 1-2 inhalations 3 times a day). For bronchial asthma, the drug should only be used as needed.

Berodual^® H in children should be used only as prescribed by a doctor and under the supervision of adults.

Method of application

Patients should be instructed about the proper use of the metered-dose aerosol. Before using the new inhaler for the first time, take the inhaler bottom up, remove the protective cap and make 2 injections into the air by pressing the bottom of the can 2 times.

Each time you use a metered-dose aerosol, you must observe the following rules::

1. Remove the protective cap.

2. Make a slow, full exhalation.

3. While holding the inhaler, as shown in Figure 1, tightly wrap your lips around the mouthpiece. The spray can should be directed with the bottom and the arrow pointing up.

Figure 1

4. Start inhaling and simultaneously press hard on the bottom of the can until one inhalation dose is released.

Continue to inhale slowly to the maximum and hold your breath for a few seconds. Then remove the mouthpiece from your mouth and exhale slowly.

To obtain a second inhaled dose, repeat the steps from step 2.

5. Put on the protective cap.

6. If the aerosol can has not been used for more than 3 days, press the bottom of the can once before use until the aerosol cloud appears.

Since the can is opaque, it is impossible to determine visually whether it is empty. The canister is designed for 200 inhalations. After using this number of doses, a small amount of the solution may remain in it. However, you should replace the inhaler, because otherwise you may not get the necessary therapeutic dose.

The amount of the drug remaining in the can can be checked as follows:

- shake the can, this will show if there is any liquid left in it,

- another way. Remove the plastic mouthpiece from the canister and place the canister in a container of water. The contents of the can can be determined by its position in the water (see Figure 2).

Figure 2

Clean the inhaler at least once a week.

It is important to keep the inhaler mouthpiece clean so that the drug particles do not block the release of the aerosol.

During cleaning, first remove the protective cap and remove the canister from the inhaler. Pass a stream of warm water through the inhaler, make sure that the drug and/or visible dirt are removed.

Figure 3

After cleaning, shake the inhaler and allow it to air dry without using heating devices. Once the mouthpiece is dry, insert the canister into the inhaler and put on the protective cap.

Figure 4

Warning: the plastic mouthpiece is specially designed for the metered aerosol Berodual^® H and is used for accurate dosing of the drug. The mouthpiece should not be used with other metered-dose aerosols. Also, you can not use the aerosol Berodual^® N With any adapters other than the mouthpiece supplied with the spray can.

The contents of the canister are under pressure. The canister must not be opened and subjected to heat above 50 °C.

Inhaled.

Treatment should be carried out under medical supervision (for example, in a hospital setting). Treatment at home is possible only after consultation with a doctor in cases where a fast-acting beta-agonist at a low dose is not effective enough. Also, the solution for inhalation can be recommended to patients in the case when the aerosol for inhalation can not be used or if it is necessary to use higher doses. The dose should be selected individually, depending on the severity of the attack. Treatment should usually begin with the lowest recommended dose and stop after a sufficient reduction in symptoms has been achieved.

The following doses are recommended.

Adults (including the elderly) and adolescents over 12 years of age

Acute attacks of bronchospasm. Depending on the severity of the attack, the doses can vary from 1 ml (1 ml = 20 drops) to 2.5 ml (2.5 ml = 50 drops). In particularly severe cases, it is possible to use doses up to 4 ml (4 ml = 80 drops).

Children 6-12 years old

Acute attacks of bronchial asthma. Depending on the severity of the attack, the doses can vary from 0.5 ml (0.5 ml = 10 drops) to 2 ml (2 ml = 40 drops).

Children under 6 years of age (whose body weight is less than 22 kg)

Due to the fact that information about the use of the drug in this age group is limited, it is recommended to use the following dose (only under medical supervision): 0.1 ml (2 drops)/kg of body weight, but not more than 0.5 ml (10 drops).

The inhalation solution should only be used for inhalation (with a suitable nebulizer) and should not be administered orally.

Treatment should usually begin with the lowest recommended dose.

The recommended dose should be diluted with 0.9% sodium chloride solution to a final volume of 3-4 ml, and applied (completely) with a nebulizer.

Atrovent Beta Solution^® for inhalation, it should not be diluted with distilled water.

Dilution of the solution should be carried out every time before use, the remains of the diluted solution should be destroyed.

The diluted solution should be used immediately after preparation. The duration of inhalation can be controlled by the consumption of the diluted solution.

Atrovent Beta Solution^® for inhalation, it can be used using various commercial models of nebulizers. The dose reaching the lungs and the systemic dose depend on the type of nebulizer used and may be higher than the corresponding doses when using Atrovent Beta metered-dose aerosol^® N (which depends on the type of inhaler). When using a centralized oxygen system, the solution is best used at a flow rate of 6-8 l/min.

Follow the instructions for use, maintenance and cleaning of the nebulizer.

hypersensitivity to phenoterol hydrobromide, atropine-like substances or any other components of the drug,

hypertrophic obstructive cardiomyopathy,

tachyarrhythmia,

pregnancy (first trimester),

children under 6 years of age.

With caution: angle-closure glaucoma, coronary insufficiency, arterial hypertension, insufficiently controlled diabetes mellitus, recent myocardial infarction, severe organic heart and vascular diseases, hyperthyroidism, pheochromocytoma, prostatic hypertrophy, bladder neck obstruction, cystic fibrosis, childhood.

Hypertrophic obstructive cardiomyopathy, tachyarrhythmia, hypersensitivity to phenoterol hydrobromide, atropine-like substances or any other components of the drug, the first trimester of pregnancy, children under 6 years of age. With caution: angle-closure glaucoma, coronary insufficiency, arterial hypertension, insufficiently controlled diabetes mellitus, recent myocardial infarction, severe organic heart and vascular diseases, hyperthyroidism, pheochromocytoma, prostatic hypertrophy, bladder neck obstruction, cystic fibrosis, childhood.

hypersensitivity to ipratropium bromide and phenoterol, atropine-like substances or any other components of the drug,

hypertrophic obstructive cardiomyopathy,

tachyarrhythmia,

pregnancy (I trimester).

With caution: angle-closure glaucoma, arterial hypertension, insufficiently controlled diabetes mellitus, recent myocardial infarction, severe organic heart and vascular diseases, ischemic heart disease, hyperthyroidism, pheochromocytoma, urinary tract obstruction, cystic fibrosis, pregnancy (II and III trimesters), breastfeeding.

Many of these undesirable effects may be due to the anticholinergic and beta-adrenergic properties of the drug. Berodual^® H, like any inhalation therapy, can cause local irritation. Adverse reactions of the drug were determined on the basis of data obtained in clinical studies and during pharmacological supervision of the use of the drug after its registration.

The most common side effects reported in clinical studies were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased sAD, and nervousness.

The frequency of adverse reactions that may occur during therapy is given as the following gradation: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1, 000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), unspecified frequency (frequency cannot be estimated from available data).

On the part of the immune system: rarely* - anaphylactic reaction, hypersensitivity.

From the side of metabolism and nutrition: rarely * - hypokalemia.

Mental disorders: infrequently-nervousness, rarely-agitation, mental disorders.

From the nervous system: infrequently-headache, tremor, dizziness.

On the part of the visual organ: rarely* - glaucoma, increased IOP, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, the appearance of a halo around objects.

From the CCC side: infrequently-increased heart rate, tachycardia, palpitation, rarely-arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia*.

Respiratory, thoracic, and mediastinal disorders: often-cough, infrequently-pharyngitis, dysphonia, rarely-bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm*, dry throat*.

From the gastrointestinal tract: infrequently-vomiting, nausea, dry mouth, rarely — stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation*, oral edema*.

From the skin and subcutaneous tissues: rarely — urticaria, itching, rash, angioedema, hyperhidrosis*.

From the musculoskeletal system and connective tissue: rarely-muscle weakness, muscle spasm, myalgia.

From the kidneys and urinary tract: rarely-urinary retention.

Laboratory and instrumental data: infrequently - increase in sAD, rarely-increase in dBP.

* These adverse reactions were not detected during clinical trials of the drug Berodual^® H. The assessment was based on the upper bound of 95% CI calculated for the general patient population.

Many of these undesirable effects may be due to the anticholinergic and beta-adrenergic properties of the drug. Atrovent Beta^® as with any inhalation therapy, it can cause local irritation. Adverse reactions of the drug were determined on the basis of data obtained in clinical studies and during pharmacological supervision of the use of the drug after its registration.

The most common side effects reported in clinical studies were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased sAD, and nervousness.

The frequency of adverse reactions that may occur during therapy is given as the following gradation: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (frequency cannot be estimated from available data).

On the part of the immune system: rarely* - anaphylactic reaction, hypersensitivity.

From the side of metabolism and nutrition: rare* — hypokalemia, very rarely — an increase of glucose in blood serum.

Mental disorders: infrequently-nervousness, rarely-agitation, mental disorders.

From the nervous system: infrequently-headache, tremor, dizziness, frequency unknown-hyperactivity.

On the part of the visual organ: rarely* - glaucoma, increased IOP, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, the appearance of a halo around objects.

From the CCC side: infrequently-tachycardia, palpitation, rarely-arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia*.

Respiratory, thoracic, and mediastinal disorders: often-cough, infrequently-pharyngitis, dysphonia, rarely-bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm*, dry throat*.

From the gastrointestinal tract: infrequently-vomiting, nausea, dry mouth, rarely-stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation*, oral edema*, heartburn.

From the skin and subcutaneous tissues: rarely — urticaria, itching, angioedema*, hyperhidrosis*, rash, petechiae.

From the musculoskeletal system and connective tissue: rarely-muscle weakness, muscle spasm, myalgia.

From the kidneys and urinary tract: rarely-urinary retention.

Laboratory and instrumental data: infrequently - increase in sAD, rarely-increase in dBP.

* These adverse reactions were not detected during clinical trials of Atrovent Beta^®. The assessment was based on the upper bound of 95% CI calculated for the general patient population.

Symptoms: usually associated primarily with the action of fenoterol.

There may be symptoms associated with excessive stimulation of beta-adrenergic receptors. The most likely occurrence of tachycardia, palpitations, tremors, hypertension or hypotension, increased pulse pressure, angina, arrhythmias and hot flashes, metabolic acidosis, hypokalemia.

Symptoms overdoses of ipratropium bromide (such as dry mouth, impaired eye accommodation), given the large breadth of the therapeutic effect of the drug and the local method of application, are usually low-expressed and have a transient character.

Treatment: it is necessary to stop taking the drug. It is necessary to take into account the data of monitoring the acid-base balance of the blood. Sedatives, tranquilizers, and in severe cases, intensive therapy are indicated. As a specific antidote, beta-blockers may be used, preferably beta-blockers.₁- selective adrenoblockers. However, you should be aware of the possible increase in bronchial obstruction under the influence of beta-blockers and carefully select the dose for patients suffering from bronchial asthma or COPD, due to the risk of severe bronchospasm, which can lead to death.

Symptoms: they are mainly associated with the action of fenoterol. There may be symptoms associated with excessive stimulation of beta-adrenergic receptors. The most likely occurrence is tachycardia, palpitations, tremors, increased blood pressure, decreased blood pressure, increased differences between sAD and dAD, angina, arrhythmia, and hot flashes. Metabolic acidosis and hypokalemia were also observed.

The symptoms of an overdose of ipratropium bromide (such as dry mouth, impaired eye accommodation), given the large breadth of the therapeutic effect of the drug and the local method of administration, are usually mild and transient.

Treatment: it is necessary to stop taking the drug. It is necessary to take into account the data of monitoring the acid-base balance of the blood. Sedatives, tranquilizers, and in severe cases, intensive therapy are indicated. As a specific antidote, beta-blockers may be used, preferably beta-blockers.₁- selective adrenoblockers. However, you should be aware of the possible increase in bronchial obstruction under the influence of beta-blockers and carefully select the dose for patients suffering from bronchial asthma or COPD, due to the risk of severe bronchospasm, which can lead to death.

Berodual^® H contains two components that have bronchodilatory activity: ipratropium bromide-m-holinoblokator and phenoterol hydrobromide-β₂- adrenomimetic.

Bronchodilation with inhaled administration of ipratropium bromide is mainly due to local, rather than systemic anticholinergic action.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. Ipratropium bromide inhibits reflexes caused by the vagus nerve. Anticholinergic agents prevent an increase in intracellular Ca concentration² , which occurs due to the interaction of acetylcholine with the muscarinic receptor located on the smooth muscles of the bronchi. The Release Of Ca² It is mediated by a system of secondary mediators, which include inositol triphosphate (ITP) and diacylglycerin (DAG).

In patients with bronchospasm associated with COPD (chronic bronchitis and emphysema), significant improvement in lung function (an increase in FEV1 and peak expiratory velocity by 15% or more) was observed within 15 minutes, the maximum effect was achieved after 1-2 hours and continued in most patients up to 6 hours after administration.

Ipratropium bromide does not adversely affect mucus secretion in the respiratory tract, mucociliary clearance, and gas exchange.

Phenoterol hydrobromide selectively stimulates β₂- adrenoreceptors in a therapeutic dose. Β stimulation₂-adrenergic receptors activates adenylate cyclase via stimulation of the G_s- squirrel.

Β stimulation₁- adrenoreceptor activity occurs when high doses are used.

Fenoterol hydrobromide relaxes the smooth muscles of the bronchi and blood vessels and counteracts the development of bronchospastic reactions caused by the influence of histamine, metacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory mediators and bronchial obstruction from mast cells. In addition, when using fenoterol at doses of 0.6 mg, an increase in mucociliary clearance was noted.

the beta-adrenergic effect of the drug on cardiac activity, such as an increase in the frequency and strength of heart contractions, is due to the vascular action of fenoterol, the stimulation of β₂- adrenoreceptors of the heart, and when using doses exceeding the therapeutic ones, by stimulating β₁- adrenergic receptors.

As with the use of other beta-adrenergic drugs, there was an elongation of the QTc interval when using high doses. When using phenoterol with metered-dose aerosol inhalers (DAI), this effect was not constant and was observed in the case of doses that exceeded the recommended ones. However, after the use of fenoterol with nebulizers (solution for inhalation in vials with a standard dose), the systemic effect may be higher than when using the drug with DAI in the recommended doses.

The clinical significance of these observations has not been established. The most commonly observed effect of beta-adrenoreceptor agonists is tremor. In contrast to the effects on the smooth muscles of the bronchi, tolerance can develop to the systemic effects of beta-adrenoreceptor agonists, the clinical significance of this manifestation has not been clarified. Tremor is the most common undesirable effect when using beta-adrenoreceptor agonists. When these two active substances are used together, the bronchodilating effect is achieved by acting on various pharmacological targets. These substances complement each other, as a result, the antispasmodic effect on the muscles of the bronchi increases and a greater breadth of therapeutic action is provided for bronchopulmonary diseases accompanied by constriction of the respiratory tract. The complementary effect is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, which allows you to individually select an effective dose with virtually no side effects. In acute bronchoconstriction, the effect of the drug Berodual^® H develops quickly, which allows it to be used in acute attacks of bronchospasm.

The Drug Atrovent Beta^® it contains two components that have bronchodilatory activity: ipratropium bromide-m-holinoblokator and phenoterol-β₂- adrenomimetic. Bronchodilation with inhaled administration of ipratropium bromide is mainly due to local, rather than systemic, anticholinergic action.

Ipratropium bromide is a quaternary ammonium derivative with anticholinergic (parasympatholytic) properties. The drug inhibits the reflexes caused by the vagus nerve, counteracting the effects of acetylcholine-a mediator released from the endings of the vagus nerve. Anticholinergic agents prevent an increase in intracellular Ca concentration² , which occurs due to the interaction of acetylcholine with the muscarinic receptor located on the smooth muscles of the bronchi. The Release Of Ca² It is mediated by a system of secondary mediators, which include inositol triphosphate (ITP) and diacylglycerin (DAG).

In patients with bronchospasm associated with chronic obstructive pulmonary diseases (chronic bronchitis and emphysema), a significant improvement in lung function (an increase in FEV1 and peak expiratory velocity by 15% or more) was observed within 15 minutes, the maximum effect was achieved after 1-2 hours and continued in most patients up to 6 hours after administration.

Ipratropium bromide does not adversely affect mucus secretion in the respiratory tract, mucociliary clearance, and gas exchange.

Phenoterol selectively stimulates β₂- adrenoreceptors in a therapeutic dose. Β stimulation₂-adrenergic receptors activates adenylate cyclase via stimulation of the G_s- squirrel. Β stimulation₁- adrenergic receptors occur when using high doses.

Fenoterol relaxes the smooth muscles of the bronchi and blood vessels and counteracts the development of bronchospastic reactions caused by the influence of histamine, metacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory mediators and bronchial obstruction from mast cells. In addition, when using fenoterol at doses of 0.6 mg, an increase in mucociliary clearance was noted.

the beta-adrenergic effect of the drug on cardiac activity, such as an increase in the frequency and strength of heart contractions, is due to the vascular action of fenoterol, the stimulation of β₂- adrenoreceptors of the heart, and when using doses exceeding the therapeutic ones, by stimulating β₁- adrenergic receptors.

As with the use of other beta-adrenergic drugs, there was an elongation of the QTc interval when using high doses. When using phenoterol with metered-dose aerosol inhalers (DAI), this effect was not constant and was observed in the case of doses that exceeded the recommended ones.

However, after the use of fenoterol with nebulizers (solution for inhalation in vials with a standard dose), the systemic effect may be higher than when using the drug with DAI in the recommended doses. The clinical significance of these observations has not been established. The most commonly observed effect of beta-adrenoreceptor agonists is tremor. In contrast to the effects on the smooth muscles of the bronchi, systemic effects of beta-adrenoreceptor agonists can develop tolerance. The clinical significance of this manifestation has not been clarified. Tremor is the most common undesirable effect when using beta-adrenoreceptor agonists. When these two active substances are used together, the bronchodilating effect is achieved by acting on various pharmacological targets. These substances complement each other, as a result, the antispasmodic effect on the muscles of the bronchi increases and a greater breadth of therapeutic action is provided for bronchopulmonary diseases accompanied by constriction of the respiratory tract. The complementary effect is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, which allows you to individually select an effective dose with the practical absence of side effects of the drug Atrovent Beta^®. In acute bronchoconstriction, the effect of Atrovent Beta^® it develops quickly, which allows it to be used in acute attacks of bronchospasm.

The therapeutic effect of the combination of ipratropium bromide and phenoterol hydrobromide is a consequence of its local action in the respiratory tract. The development of bronchodilation is not parallel to the pharmacokinetic parameters of active substances.

After inhalation, 10-30% of the administered dose of the drug usually enters the lungs (depending on the dosage form and method of inhalation). The remaining portion of the dose is deposited on the mouthpiece, in the oral cavity and oropharynx. Part of the dose deposited in the oropharynx is swallowed and enters the gastrointestinal tract.

Part of the dose of the drug that enters the lungs quickly reaches the systemic blood flow (within a few minutes).

There is no evidence that the pharmacokinetics of the combined drug differs from that of each of the individual components.

Fenoterol hydrobromide

The ingested portion of the dose is metabolized to sulfate conjugates. Absolute oral bioavailability is low (about 1.5%).

After intravenous administration, free and conjugated phenoterol make up 15 and 27% of the administered dose, respectively, in a 24-hour urine analysis. After inhalation, approximately 1% of the administered dose is excreted in the form of free phenoterol in a 24-hour urine test. On this basis, the total systemic bioavailability of the inhaled dose of fenoterol hydrobromide is estimated at 7%.

The kinetic parameters describing the distribution of phenoterol are calculated from the plasma concentration after intravenous administration. After intravenous administration, the plasma concentration-time profiles can be described by a three-part model, according to which T_1/2 is approximately 3 h. In this three-part model, the apparent V_ss phenoterol approximately 189 l (»2.7 l / kg).

About 40% of fenoterol binds to plasma proteins. Preclinical studies have shown that phenoterol and its metabolites do not penetrate the BBB. Total clearance of fenoterol-1.8 l / min, renal clearance-0.27 l / min. The total renal excretion (within 2 days) of the isotope-labeled dose (including the starting compound and all metabolites) was 65% after intravenous administration. The total isotope-labeled dose released through the intestine was 14.8% after intravenous administration, and 40.2% after oral administration for 48 hours. The total isotope-labeled dose released through the kidneys was about 39% after oral administration.

Ipratropium bromide

The total renal excretion (within 24 h) of the starting compound is approximately 46% of the intravenous dose, less than 1% of the oral dose, and approximately 3-13% of the inhaled dose of the drug. Based on these data, it is calculated that the total systemic bioavailability of ipratropium bromide, used orally and inhaled, is 2 and 7-28%, respectively. Thus, the effect of the ingested part of ipratropium bromide on the systemic effect is insignificant.

The kinetic parameters describing the distribution of ipratropium bromide were calculated based on its plasma concentrations after intravenous administration. A rapid two-phase decrease in plasma concentration is observed. The Apparent V_ss it is approximately 176 l (»2.4 l / kg). The drug binds to plasma proteins to a minimal extent (less than 20%). Preclinical studies have shown that ipratropium, which is a quaternary compound of ammonium, does not penetrate the BBB.

T_1/2 In the final phase, it is approximately 1.6 hours. The total clearance of ipratropium is 2.3 l / min, and the renal clearance is 0.9 l / min. After intravenous administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver.

The total renal excretion (within 6 days) of the isotope-labeled dose (including the starting compound and all metabolites) was 72.1% after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation. The total isotope-labeled dose released through the intestine was 6.3% after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation. Thus, the excretion of the isotope-labeled dose after intravenous administration is mainly carried out through the kidneys. T_1/2 the initial compound and metabolites is 3.6 hours. The main metabolites excreted in the urine bind weakly to muscarinic receptors and are considered inactive.

The therapeutic effect of the combination of ipratropium bromide and fenoterol is a consequence of its local action in the respiratory tract. The development of bronchodilation is not directly proportional to the pharmacokinetic parameters of active substances.

After inhalation, 10-39% of the administered dose of the drug usually enters the lungs (depending on the dosage form and method of inhalation). The remaining portion of the dose is deposited on the mouthpiece, in the oral cavity and oropharynx. Part of the dose deposited in the oropharynx is swallowed and enters the gastrointestinal tract.

Part of the dose of the drug that enters the lungs quickly reaches the systemic blood flow (within a few minutes).

There is no evidence that the pharmacokinetics of the combined drug differs from that of each of the individual components.

Fenoterol

The ingested portion of the dose is metabolized to sulfate conjugates. Absolute oral bioavailability is low (about 1.5%).

After intravenous administration, free and conjugated phenoterol make up 15 and 27% of the administered dose, respectively, in a 24-hour urine analysis. The total systemic bioavailability of the inhaled dose of fenoterol is estimated at 7%.

The kinetic parameters describing the distribution of phenoterol are calculated from the plasma concentration after intravenous administration. After intravenous administration, the plasma concentration-time profiles can be described by a 3-chamber pharmacokinetic model, according to which T_1/2 is approximately 3 hours. In this 3-chamber model, the apparent V_ss phenoterol approximately 189 l (»2.7 l / kg).

About 40% of fenoterol binds to plasma proteins.

Preclinical studies have shown that phenoterol and its metabolites do not penetrate the BBB. Total clearance of fenoterol-1.8 l / min, renal clearance-0.27 l / min. The total renal excretion (within 2 days) of the isotope-labeled dose (including the starting compound and all metabolites) was 65% after intravenous administration. The total isotope-labeled dose released through the intestine was 14.8% after intravenous administration, and 40.2% after oral administration for 48 hours. The total isotope-labeled dose released through the kidneys was about 39% after oral administration.

Ipratropium bromide

Total renal excretion (within 24 h) of the parent compound is approximately 46% of the value/administered dose, less than 1% of the dose used in, and in about 3-13% of the inhaled dose. Based on these data, it is calculated that the total systemic bioavailability of ipratropium bromide, used orally and inhaled, is 2 and 7-28%, respectively. Thus, the effect of the ingested part of ipratropium bromide on the systemic effect is insignificant.

The kinetic parameters describing the distribution of ipratropium bromide are calculated based on its plasma concentrations after intravenous administration. A rapid two-phase decrease in plasma concentration is observed. The Apparent V_ss it is approximately 176 l (»2.4 l / kg). The drug binds to plasma proteins to a minimal extent (less than 20%). Preclinical studies have shown that ipratropium bromide, which is a quaternary derivative of ammonium, does not penetrate the BBB.

T_1/2 in the final phase, it is approximately 1.6 hours.

The total clearance of ipratropium bromide is 2.3 l / min, and the renal clearance is 0.9 l / min. After intravenous administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver.

The total renal excretion (within 6 days) of the isotope-labeled dose (including the starting compound and all metabolites) was 72.1% after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation. The total isotope-labeled dose released through the intestine was 6.3% after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation. Thus, the excretion of the isotope-labeled dose after intravenous administration is mainly carried out through the kidneys.

T_1/2 the initial compound and metabolites is 3.6 hours. The main metabolites excreted in the urine bind weakly to muscarinic receptors and are considered inactive.

Long-term simultaneous use of the drug Berodual^® H with other anticholinergic drugs is not recommended due to the lack of data.

beta-adrenergic and anticholinergic agents, xanthine derivatives (for example, theophylline) can enhance the bronchodilating effect of Berodual^® H. Concomitant administration of other beta-adrenomimetics that enter the systemic circulation of anticholinergics or xanthine derivatives (for example, theophylline) may lead to increased side effects. There may be a significant weakening of the bronchodilating effect of the drug Berodual^® H with simultaneous administration of beta-blockers.

Hypokalemia associated with the use of beta-adrenomimetics can be enhanced by the simultaneous administration of xanthine derivatives, corticosteroids and diuretics. This should be given special attention in the treatment of patients with severe forms of obstructive respiratory diseases.

Hypokalemia may lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on the heart rate. In such cases, it is recommended to monitor the concentration of potassium in the blood serum.

Caution should be exercised when prescribing β₂- adrenergic agents in patients treated with MAO inhibitors and tricyclic antidepressants, since these drugs can enhance the effect of beta-adrenergic agents.

Inhalation of halogenated hydrocarbon anesthetics, such as halothane, trichloroethylene, or enflurane, may increase the adverse effects of beta-adrenergic agents on CCC.

Long-term simultaneous use of Atrovent Beta^® with other anticholinergic drugs, it is not recommended due to the lack of data.

beta-adrenergic and anticholinergic agents, xanthine derivatives (for example, theophylline) may enhance the bronchodilating effect of Atrovent Beta^®. Concomitant use of other beta-adrenomimetics, anticholinergics, or xanthine derivatives (e.g., theophylline) may lead to increased side effects.

Hypokalemia associated with the use of beta-adrenomimetics can be enhanced by the simultaneous administration of xanthine derivatives, corticosteroids and diuretics. This should be given special attention in the treatment of patients with severe forms of obstructive respiratory diseases.

Hypokalemia may lead to an increased risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on the heart rate. In such cases, it is recommended to monitor the level of potassium in the blood serum.

Caution should be exercised when prescribing β₂- adrenergic agents in patients treated with MAO inhibitors and tricyclic antidepressants, since these drugs can enhance the effect of beta-adrenergic agents.

Inhalation of halogenated hydrocarbon anesthetics, such as halothane, trichloroethylene, or enflurane, may increase the effect of beta-adrenergic agents on CCC.

Co-administration of Atrovent Beta^® with cromoglycic acid and / or corticosteroids increases the effectiveness of therapy.