Ipratropium, Fenoterol

Pharmacological properties

Berodual N contains two active bronchodilator ingredients: ipratropium bromide, which has an anticholinergic effect, and phenoterol hydrobromide, which is a β-adrenergic agonist.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatolytic) properties. It inhibits vagal reflexes due to antagonistic interaction with acetylcholine, a mediator that provides transmission of the vagus nerve impulse. Anticholinergics prevent an increase in intracellular Ca concentration²⁺resulting from the interaction of acetylcholine with muscarinic receptors of smooth muscles. Ca release²⁺ the second mediator system, consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol) contributes.

The expansion of the bronchi after inhalation of ipratropium bromide is mainly due to the local, specific action of the drug, and is not systemic.

Fenoterol hydrobromide is a direct sympathomimetic that selectively stimulates β in the therapeutic range₂-adrenoreceptors. When using high doses, β is stimulated₁-adrenoreceptors. The binding of β₂-adrenoreceptors with the help of an activating Gs-protein leads to the activation of adenylate cyclase. With an increase in cAMP, protein kinase A is activated and the corresponding proteins are phosphorylated in smooth muscle cells. In turn, this determines the phosphorylation of myosin light chain kinase, blocking the hydrolysis of phosphoinositide and the opening of large calcium-dependent potassium channels.

Fenoterol hydrobromide relaxes the bronchial and vascular smooth muscles and protects against bronchoconstriction stimulants such as histamine, methacholine, cold air, and allergens (immediate type reactions). After a single dose, fenoterol blocks the release of bronchoconstrictor and pro-inflammatory mediators from stem cells. In the future, after taking fenoterol at a dose of 0.6 μg, an improvement in mucociliary clearance was noted.

With a higher concentration of fenoterol in blood plasma, which is most often achieved with oral administration or even iv, a decrease in uterine contractility is noted. Also, when using high doses, the metabolic effect of the drug is possible: lipolysis, glycogenolysis, hyperglycemia and hypokalemia, the latter is caused by increased uptake of K⁺, especially in skeletal muscle. β-adrenergic effects of phenoterol on the heart, including increased heart rate and heart rate, are associated with the vascular effects of phenoterol, stimulation of β₂-adrenoreceptors of the heart, and with supra-therapeutic doses - with stimulation of β₁-adrenoreceptors. As with other β-adrenergic agents, an extension of the Q – Tc interval is noted. For phenoterol in the form of a metered aerosol, these indicators are discrete and are observed at doses higher than recommended. However, the systemic effect of phenoterol after use with a nebulizer (solution for inhalation) may be higher than when using the recommended doses of a dosed aerosol. Clinical relevance not established. An undesirable effect most often noted for β-mimetics is tremor. In contrast to the effect on bronchial smooth muscles, the systemic effects of β-mimetics are the reason for the development of tolerance.

With the simultaneous use of two active bronchodilators, the expansion of the bronchi occurs through the implementation of two different pharmacological mechanisms. Thus, the two active substances have a combined antispasmodic effect on the bronchial muscles, which allows them to be widely used in diseases of the bronchopulmonary apparatus associated with impaired airway patency.For the effectiveness of the combined action, a very small amount of β-mimetic is required, which allows you to select the dosage regimen of the drug individually for each patient and minimize the number of side effects.

Pharmacokinetics The therapeutic effect of the combination of ipratropium bromide and phenoterol hydrobromide is manifested by local exposure to the respiratory tract. Therefore, the pharmacokinetics of bronchodilation is not associated with that of the active ingredients of the drug.

After inhalation, about 10–39% of the dose of the drug as a whole settles in the lungs, depending on the form of release, inhalation technique and device, and the rest remain on the tip of the inhaler, in the mouth and upper respiratory tract (oropharynx).

There is no evidence that the pharmacokinetics of the combination of both ingredients is different from that of monosubstances.

Fenoterol hydrobromide. The part of the drug that is swallowed is mainly metabolized to sulfate conjugates. Absolute bioavailability after oral administration is low (about 1.5%).

After iv administration, the proportion of free fenoterol and conjugated fenoterol reaches 15 and 27% of the administered dose in daily urine, respectively. After inhalation using a metered-dose aerosol, Berodual N approximately 1% of the inhaled dose is excreted in the form of free phenoterol with daily urine. According to this, it was found that the total systemic bioavailability of inhaled doses of phenoterol hydrobromide is 7%.

The kinetic parameters characterizing the phenoterol disposition were calculated according to the concentration of phenoterol in blood plasma after iv administration. After iv administration, the indicators “plasma concentration - time” can be described using a three-chamber model, where the terminal T_½ is about 3 hours. According to this three-chamber model, the expected volume of phenoterol distribution in a stable state (V_dss) is about 189 l (≈2.7 l / kg).

About 40% of the drug binds to plasma proteins. Preclinical animal studies have shown that fenoterol and its metabolites pass through the BBB. The total clearance of fenoterol is 1.8 l / min, and the renal clearance is 0.27 l / min.

In the study of the balance of excretion, the total renal clearance (2 days) of the radioactive drug (including the maternal compound and all metabolites) was 65% of the dose after iv administration, and the total level of radioactivity in the feces was 14.8% of the dose. After oral administration, the total level of radioactivity in the urine was about 39% of the dose, and the total level of radioactivity in the feces was 40.2% of the dose for 48 hours.

Ipratropium bromide. Cumulative renal excretion (0–24 h) of ipratropium (the parent compound) was about 46% of the dose after iv administration, 1% after oral administration and about 3–13% after inhalation using a metered-dose inhaler Berodual N. Based on these data , it can be argued that the total systemic bioavailability after oral and inhalation administration of ipratropium bromide is estimated to be 2 and 7–28%, respectively. So, the part of the dose of ipratropium bromide that is swallowed will not significantly affect the systemic effect.

The kinetic parameters characterizing the disposition of ipratropium are calculated based on its concentration after iv administration. A rapid two-phase decrease in the concentration of the drug in blood plasma was recorded. Apparent volume of distribution in steady state (V_dss) is about 176 l (≈2.4 l / kg). The drug in a minimal amount (less than 20%) binds to plasma proteins. Preclinical animal studies indicate that the quaternary amine of ipratropium does not pass through the BBB.

T_½ the final elimination phase is about 1.6 hours. The total clearance of ipratropium is 2.3 l / min, renal clearance is 0.9 l / min.After iv administration, about 60% is metabolized, probably mainly in the liver by oxidation.

During the study of the balance of excretion, the total renal clearance (6 days) of the radioactive drug (including the maternal compound and all metabolites) amounted to 72.1% of the dose after iv administration, 9.3% after oral administration and 3.2% after inhalation use. The total level of radioactivity in feces was 6.3% of the dose after iv administration, 88.5% after oral administration and 69.4% after inhalation. The main route of excretion of a radioactive drug after iv administration is the kidneys. T_½ the elimination of the radioactive drug (the parent compound and all metabolites) is 3.6 hours. The binding of the main urine metabolites to muscarinic receptors is negligible, and the metabolites should be considered ineffective.

Indications

Prevention and symptomatic treatment of chronic obstructive airway disorders: allergic and non-allergic (endogenous) ba, asthma caused by physical exertion, and chronic obstructive bronchitis with or without emphysema; preparation for "lung opening" and support for aerosol therapy with corticosteroids, mucolytics, saline, rum, cromoglicic acid and antibiotics.

With prolonged therapy, concomitant anti-inflammatory therapy should be prescribed.

Application

The dose is selected depending on the nature and severity of the disease. for adults and children over 6 years of age, the following dosage regimens are recommended.

To stop an acute attack of bronchospasm and an attack of dyspnea, an inhalation of a dose of 100 μg of phenoterol hydrobromide and 40 μg of ipratropium bromide is recommended (2 inhalations). In total, with an acute attack of dyspnea, 1 inhalation is enough to quickly facilitate breathing. If, after 5 minutes, breathing does not significantly improve after 1–2 inhalations, 1–2 additional inhalations can be given. If there is no effect after 4 inhalations, it may be necessary to carry out additional measures. In such cases, the patient should immediately consult a doctor.

If it is considered necessary to use Berodual N for long-term treatment, the recommended dose is 1-2 inhalations 3-4 times a day. For asthma, metered-dose aerosol Berodual N should be used only when necessary. The time and dose of each inhalation must be determined by the symptoms. There should be an interval of at least 3 hours between inhalations. The total daily dose should not exceed 12 inhalations, since the highest dose does not add therapeutic benefits in general, but can increase the likelihood of potentially serious side effects.

To prevent an asthma attack caused by physical exertion, or expected contact with an allergen, 2 inhalations are used, if possible 10-15 minutes before the incident.

Patients should be instructed on the proper use of metered-dose aerosol to ensure successful treatment (see Procedure for Use).

The order of application. The proper use of metered-dose aerosol is important to ensure successful treatment. Patients should be instructed on the proper use of metered-dose aerosol. During inhalation, the arrow on the spray can points straight up, and the mouthpiece points down, regardless of the position of the body for inhalation. Apply if possible while sitting or standing.

Before the first use of metered-dose aerosol, it is necessary to remove the protective cap and press the valve twice.

Before each use of metered-dose aerosol, it is necessary:

1. Remove the protective cap (if the spray can is not used for more than 3 days, press the valve 1 time before use).

2. Take a deep breath.

3. Grasp the tip of the lips. The arrow on the spray can be turned up, and the mouthpiece - down.

4.Inhale as deep as possible, at the same time press the bottom of the can until the release of 1 measured dose. Hold your breath for a few seconds, then remove the tip from your mouth and exhale slowly.

5. After use, put on the protective cap.

Patients should be instructed on the proper use of metered-dose aerosol. If the can of metered-dose aerosol has not been used for more than 3 days, press the valve once before use. Avoid contact with the eyes. In children, metered-dose aerosol Berodual N should be used only on the recommendation of a doctor and under the supervision of adults.

Clean the inhaler at least 1 time per week. It is important to keep the mouthpiece of the inhaler clean to ensure that the preparation is not thickened and that nothing prevents the flow of the aerosol. To clean the inhaler, first remove the dust cap and disconnect the canister from the inhaler. The inhaler is washed with water until the thickened preparation and / or dirt are completely cleaned.

After cleaning, shake the inhaler and let it air dry without using any heating system. When the mouthpiece dries, attach the spray can and dust cap.

Warning: the mouthpiece is designed specifically for metered-dose aerosol Berodual N. The mouthpiece should not be used with any other metered-dose aerosols. Berodual N is allowed to be used only with a special mouthpiece. The contents of the can are under pressure. Do not open spray can with force.

The can is opaque. Therefore, it is impossible to see when it is empty. An aerosol can should provide 200 doses. When all of these doses are used, a little liquid may remain in the spray can. However, this spray can be replaced, otherwise it will not be possible to obtain the exact amount of the drug.

The presence of the drug in the aerosol can can be checked as follows: by shaking the can, check for fluid; disconnect the plastic mouthpiece from the can and place the can in a container of water. The contents of the aerosol can can be estimated by its position in the water.

Any unused product or waste must be disposed of.

Contraindications

Hypersensitivity to fenoterol hydrobromide or atropine-like substances, or any auxiliary substances of this drug.

Hypertrophic obstructive cardiomyopathy and tachyarrhythmia.

Side effects

Like all medicines, Berodual N can cause adverse reactions. most of the side effects below can be explained by the anticholinergic and β-adrenergic properties of berodual n.

Adverse reactions to the drug were identified on the basis of data obtained during clinical trials and pharmacovigilance during the use of the drug after registration.

The frequency of cases according to MedDRA: very often - ≥1 / 10; often - ≥1 / 100, 1/10; infrequently - ≥1 / 1000, 1/100; single - ≥1 / 10,000, 1/1000; very rarely - 1/10 000; unknown - impossible to determine from the available data.

From the side of the immune system: single - anaphylactic reactions *, hypersensitivity *; unknown - purple.

Disorders of metabolism and metabolism: single - hypokalemia *; very rarely - an increase in blood glucose.

Mental disorders: infrequently - nervousness; single - excitement, mental disorders.

Mental disorders are manifested by increased excitability, hyperactive behavior, sleep disturbances and hallucinations. This was noted mainly in children under the age of 12 years.

From the side of the nervous system: infrequently - headache, tremor, dizziness; unknown - hyperactivity.

From the side of the organ of vision: single - glaucoma *, increased intraocular pressure *, impaired accommodation *, mydriasis *, blurred vision *, eye pain *, corneal edema *, conjunctival hyperemia *, sensation of the appearance of a halo in front of the eyes *.

From the cardiovascular system: infrequently - tachycardia, accelerated heartbeat; single - arrhythmia, atrial fibrillation, supraventricular tachycardia *, myocardial ischemia *; unknown - anginal pain, ventricular extrasystole.

From the respiratory system, chest and mediastinal organs: often - cough; infrequently - pharyngitis, dysphonia; single - bronchospasm, throat irritation, pharyngeal edema, laryngospasm *, paradoxical bronchospasm * (caused by inhalation), dry throat *; unknown - local irritation.

From the digestive tract: infrequently - nausea, vomiting, dry mouth; single - stomatitis, glossitis, gastrointestinal motility **, diarrhea, constipation *, swelling of the oral cavity *, heartburn.

On the part of the skin and subcutaneous tissue: isolated - urticaria, rashes, itching, angioedema *, petechiae, hyperhidrosis *.

From the musculoskeletal system and connective tissue: single - muscle weakness, muscle cramps, myalgia.

From the kidneys and urinary system: single - urinary retention.

Research: infrequently: increase in systolic blood pressure; single - a decrease in diastolic blood pressure, thrombocytopenia.

* Adverse events not identified in any clinical study. The frequency is indicated according to the upper limit of the 95% confidence interval calculated from the total number of patients who received treatment according to the EU Guidelines for the preparation of a brief description of the drug (3/4968 = 0,00060, which means "single" phenomena).

** Especially patients with cystic fibrosis may be more likely to develop gastrointestinal motility disorders when using inhaled anticholinergic drugs (contained in Berodual N).

As with other inhalation therapy, Berodual N can cause local irritation symptoms. The most common side effects identified during clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, heart palpitations, vomiting, increased systolic blood pressure and nervousness.

special instructions

In case of acute dyspnea (difficulty breathing), which progresses rapidly, you should immediately consult a doctor.

Like other inhaled drugs, Berodual N can cause paradoxical bronchospasm, which can be life threatening. In the event of a paradoxical bronchospasm, the use of Berodual N should be discontinued and replaced with alternative therapy.

Berodual N must be used only after a thorough assessment of the benefits / benefits, especially if the dose is higher than recommended, in the following cases:

• insufficiently controlled course of diabetes;
• recent myocardial infarction;
• myocarditis;
• severe organic diseases of the heart or blood vessels (especially in the presence of tachycardia);
• hyperthyroidism;
• pheochromocytoma;
• patients who use cardiac glycosides;
• severe and untreated hypertension;
• aneurysm.

When using sympathomimetic drugs, including Berodual N, cardiovascular effects may be observed. Messages obtained from post-marketing data and scientific publications indicate isolated cases of myocardial ischemia associated with β-agonists. Patients with an underlying disease - a severe heart disease (e.g., coronary heart disease, arrhythmia, or severe heart failure) who receive Berodual N should be warned that they seek medical attention if they feel chest pain or other symptoms of worsening heart function. Consideration should be given to evaluating symptoms such as shortness of breath and chest pain, as they may be of respiratory or cardiac origin. Berodual N, like other anticholinergics, should be used with caution in patients:

• with a tendency to develop narrow-angle glaucoma;
• with existing urinary tract obstruction (e.g., with benign prostatic hyperplasia or intravesical obstruction);
• with renal failure;
• with liver failure.

There are reports of individual cases of complications from the organ of vision (mydriasis, increased intraocular pressure, narrow-angle glaucoma, pain in the eyes) resulting from contact with the eyes of an aerosol of ipratropium bromide or its combination with β₂-agonists.

Attention! Patients should be instructed in detail about the rules for using the metered-dose aerosol inhaler Berodual N. Care must be taken to avoid getting the drug in the eyes.

Signs of an acute attack of narrow-angle glaucoma include: eye pain or discomfort; blurred vision; a sense of halo; a sensation of the appearance of colored spots in front of the eyes; redness of the eye in the form of conjunctival or corneal hyperemia.

If the above symptoms appear in any combination, you should start treatment with eye drops, which contribute to the narrowing of the pupil, and immediately seek specialized medical help.

Patients with cystic fibrosis may be more likely to develop gastrointestinal motility disorders when using anticholinergics. GI motility will recover after treatment is completed.

Long-term use. In patients with AD, Berodual N should be used only if necessary. In patients with mild forms of COPD, on-demand treatment (symptomatic treatment) may be more appropriate than regular use, if circumstances permit.

It should be remembered that it is necessary to use or strengthen anti-inflammatory therapy to control the inflammatory process of the respiratory tract and to prevent the deterioration of disease control in patients with AD or steroid-dependent forms of COPD.

Regular use of high doses of a drug containing β₂-agonists, for example, Berodual N, for relief of symptoms of bronchial obstruction may lead to a deterioration in the control of the course of the disease.

In the case of increased bronchial obstruction, a simple increase in the dose of β over a long period of time₂-agonists, including Berodual N, above the recommended one is not only not justified, but also dangerous. To prevent the deterioration of the course of a life-threatening disease, consideration should be given to revising the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled corticosteroids.

Several cases of increasing the risk of serious complications of the underlying disease have been reported, as well as fatal cases with prolonged treatment of AD with excessively high doses of inhaled β₂-sympathomimetics without sufficient anti-inflammatory therapy. A causal relationship has not been fully elucidated. However, inadequate anti-inflammatory therapy is vital.

Other sympathomimetic bronchodilators should be used simultaneously with Berodual N only under medical supervision (see INTERACTIONS).

Due to excessive therapy, β₂-agonists may cause potentially serious hypokalemia (see OVERDOSAGE). With a low potassium level, it is recommended that you control the level of potassium in the blood at the beginning. Possible increase in blood glucose. Therefore, glucose levels should be monitored in patients with diabetes mellitus.

In very rare cases, after taking Berodual N, hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and anaphylactic reactions can immediately develop.

The drug contains 99% ethanol (alcohol; 100 mcg per dose). The use of Berodual N can give positive results of a doping test.

Use during pregnancy and lactation. Pregnancy. In the course of preclinical studies and clinical use of Berodual N, no negative effects of phenoterol and ipratropium on pregnancy have yet been identified.However, precautions related to the use of drugs during pregnancy must be observed.

Keep in mind the inhibitory effect of phenoterol on uterine contractility. Application β₂-sympathomimetics at the end of pregnancy or in high doses can adversely affect the baby (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia).

Lactation. Preclinical studies have shown that fenoterol passes into breast milk. There is no data on the penetration of ipratropium into breast milk. It is unlikely, especially when using an aerosol form of the drug, that ipratropium will affect the baby to a large extent. Caution is advised to prescribe Berodual N during lactation.

Fertility. There are no clinical data on the effect on the fertility of the combination of ipratropium bromide and phenoterol hydrobromide, and for each component separately. Preclinical studies of the effects of separate ipratropium bromide and phenoterol hydrobromide alone have shown no adverse effects on fertility.

Children. Used in children over the age of 6 years as prescribed by a doctor and under the supervision of adults.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies of the effect of the drug on the ability to drive a car and work with technical means have not been conducted. However, patients should be warned about the possibility of undesirable effects such as dizziness, tremors, impaired accommodation, mydriasis and blurred vision during treatment with Berodual N. Therefore, care should be taken when driving vehicles or working with equipment. When the above effects appear, patients should avoid potentially hazardous activities, such as driving vehicles or working with technical equipment.

Interactions

Long-term simultaneous use of berodual n with other anticholinergics has not been studied and therefore is not recommended.

The simultaneous administration of the following drugs / classes of drugs may affect the effect of the drug Berodual N.

Increased effect and / or increased risk of adverse reactions:

• other β-adrenergic agents (all routes of administration);
• other anticholinergics (all routes of administration);
• xanthine derivatives (e.g. theophylline);
• anti-inflammatory drugs (corticosteroids);
• MAO inhibitors;
• tricyclic antidepressants;
• halogenated carbohydrate anesthetics (e.g. halothane, trichloroethylene and enflurane). Especially they can enhance the effect on the cardiovascular system.

Decrease in effect: simultaneous administration of β-blockers.

Other possible interactions. Hypokalemia associated with the use of β-adrenergic agonists can be enhanced by the simultaneous administration of xanthine derivatives, corticosteroids and diuretics. This fact should be given special attention in the treatment of patients with severe airway disorders.

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

The risk of an acute attack of glaucoma (see SPECIAL INSTRUCTIONS) increases both when sprayed ipratropium enters the eyes, and in combination with β₂-agonists. Also, treatment with Berodual N can reduce the hypoglycemic effect of antidiabetic drugs. However, this is expected only at high doses, which are usually used for systemic administration (tablets or injections / infusions).

If you plan to use inhaled anesthetics, you should take into account that it is necessary to stop the use of phenoterol at least 6 hours before the start of anesthesia.

Overdose

Symptoms Depending on the duration of the overdose, adverse reactions typical of β2-adrenergic drugs may occur: flushing, lightheadedness, headache, tachycardia, palpitations, arrhythmia, hypotension, or even shock, ag, anxiety, chest pain, agitation, possible extrasystole and severe tremor in the fingers, as well as throughout the body. hyperglycemia may develop.

Gastrointestinal tract disorders, including nausea and vomiting, may be noted, especially after oral overdose.

When phenoterol was used in doses exceeding the recommended indications for Berodual N, metabolic acidosis and hypokalemia were noted.

Symptoms of an overdose of ipratropium bromide (dry mouth, visual disturbance) are poorly expressed due to the very low systemic bioavailability of inhaled ipratropium.

Therapy. Treatment with Berodual N should be discontinued. Acid-base balance and electrolyte monitoring should be considered. The introduction of sedatives, tranquilizers, in severe cases - intensive care, including hospitalization.

As specific antidotes for phenoterol, β-adrenoreceptor blockers, preferably β₁-selective; however, it is necessary to take into account the possible increase in bronchial obstruction under the influence of β-adrenergic receptor blockers and carefully select a dose for patients with AD or COPD due to the risk of developing acute bronchospasm, which can be fatal.

Recommended monitoring of cardiac activity, namely - ECG.

Storage conditions

At a temperature not exceeding 25 ° c. protect from direct sunlight, heat and frost.