Pharmacological properties of the drug Berotek N
Pharmacodynamics. In clinical studies lasting up to 3 months in adults with asthma, COPD and children with asthma, it was found that tetrafluoroethane and freon-containing forms of an aerosol inhaler have the same therapeutic efficacy. Fenoterol hydrobromide is a sympathomimetic agent; in a therapeutic dose, it selectively stimulates β2-adrenergic receptors; when used in higher doses, it loses its selectivity of action and stimulates β1-adrenergic receptors. The binding of the drug to β2-adrenergic receptors leads to the activation of adenylate cyclase by stimulating the Gs protein. When the concentration of cAMP increases, protein kinase A is activated, which ensures phosphorylation of target proteins in smooth muscle cells. This in turn leads to phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis and opening of large calcium-dependent potassium channels. There is evidence that large potassium channels can be activated directly by Gs protein. Fenoterol relaxes the smooth muscles of the bronchi and prevents the development of bronchospasm caused by exposure to histamine, methacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after use, fenoterol blocks the release of mediators of inflammation and bronchial obstruction from mast cells. In addition, after the use of fenoterol in higher doses, an increase in mucociliary clearance is noted. At high concentrations of the drug in the blood plasma, which is usually achieved by oral or intravenous administration, a decrease in the contractile activity of the myometrium is noted. When using the drug in high doses, metabolic effects such as lipolysis, glycogenolysis, hyperglycemia and hypokalemia have been identified; the latter is caused by increased uptake of K+ ion, primarily by skeletal muscles. The β-adrenergic effect of the drug on cardiac activity is an increase in the frequency and strength of heart contractions due to the vascular effect of fenoterol, stimulation of β2-adrenergic receptors, and when used in doses exceeding therapeutic doses, stimulation of cardiac β1-adrenergic receptors. In contrast to the effect on bronchial smooth muscle, the systemic effect of β-agonists causes the development of tolerance. Clinical studies have established the high therapeutic effectiveness of fenoterol in bronchospastic conditions. Fenoterol eliminates bronchospasm caused by various stimulants (for example, cold air), as well as immediate bronchospastic reactions upon contact with an allergen. The therapeutic effect of Berotek N is due to its local effect on the respiratory tract. The pharmacodynamic properties of bronchodilation caused by Berotec N do not relate to the pharmacokinetics of the active substance of the drug. After inhalation of fenoterol hydrobromide for obstructive pulmonary diseases, bronchodilation develops within a few minutes and lasts 3–5 hours. Depending on the method of inhalation and the inhaler used, about 10–30% of the active ingredient reaches the lower respiratory tract, while the remainder of the drug settles in the upper parts of the respiratory tract and in the oral cavity, some of it is swallowed and enters the digestive tract. After inhalation of 1 dose, about 17% of the drug is absorbed; two-phase absorption - 30% of fenoterol is rapidly absorbed with a half-absorption period of 11 minutes, and 70% is slowly absorbed with a half-absorption period of 120 minutes. There is no correlation between plasma concentrations and the pharmacodynamic response time curve after inhalation. The difference in the duration of bronchodilator action after inhalation, compared with intravenous administration, is not confirmed by systemic plasma levels. After oral administration, about 60% of fenoterol hydrobromide is absorbed and undergoes first-pass metabolism, resulting in oral bioavailability of approximately 1.5%. This is why an ingested portion of the active ingredient has virtually no effect on systemic plasma levels after inhalation. With systematic use, the elimination of fenoterol hydrobromide is three-phase with half-lives for successive phases of 0.42 minutes, 14.3 minutes and 3.2 hours. Metabolic transformation of fenoterol hydrobromide occurs almost entirely by sulfation, mainly in the intestinal wall. In unchanged form, fenoterol hydrobromide can cross the placenta and enter breast milk. There is insufficient data regarding the effect of fenoterol hydrobromide on the metabolic state in diabetes mellitus.
Instructions for use BEROTEK N (BEROTEC N)
Suction
Depending on the method of inhalation and the inhalation system used, about 10-30% of the active substance released from the aerosol preparation after inhalation reaches the lower respiratory tract, and the rest is deposited in the upper respiratory tract and in the mouth. As a result, some amount of inhaled fenoterol enters the gastrointestinal tract. The absolute bioavailability of fenoterol after inhalation of one dose of BEROTEKA® N is 18.%. Absorption from the lungs is two-phase:
- 30% of fenoterol hydrobromide is rapidly absorbed with a T1/2 of 11 minutes, and 70% is absorbed slowly with a T1/2 of 120 minutes.
Cmax of the drug in blood plasma (Cmax 45.3 pg/ml) was observed 15 minutes after a single inhalation of 100 mcg of fenoterol using a metered-dose inhaler with freon in patients with bronchial asthma. However, in studies involving healthy volunteers, in which blood tests were taken more frequently, it was found that serum Cmax of the drug was achieved earlier: 2 and 3.5 minutes after dosing. Cmax of the drug in serum after inhalation of a single dose of fenoterol 200 mcg using an HFA metered dose inhaler:
- Cmax 66.9 pg/ml, tmax15 minutes.
The therapeutic effect of BEROTEK N is achieved by its local action on the airways. Thus, Cmax in blood plasma is not necessarily related to the bronchodilator effect.
After oral administration, the degree of absorption is 60% of the administered dose of fenoterol hydrobromide. This amount undergoes extensive first-pass metabolism, resulting in a bioavailability of approximately 1.5%. Thus, the ingested portion of the active substance has only a minor effect on Cmax in blood plasma after inhalation.
Distribution
Fenoterol is distributed throughout the body. The volume of distribution at steady state after intravenous administration (Vss) is 1.9-2.7 l/kg. Vd of fenoterol in blood plasma after intravenous administration occurs according to a three-phase pharmacokinetic model. T1/2 are tα= 0.2 minutes, tβ= 14.3 minutes and tγ= 3.2 hours. Plasma protein binding ranges from 40 to 55%.
Metabolism
The biotransformation of fenoterol hydrobromide in humans occurs through conjugation with sulfates. Following oral administration, fentorerol is metabolized primarily through sulfation. This metabolic inactivation of the parent substance begins already in the intestinal walls.
Removal
Biotransformation, including biliary excretion, is due mainly (approximately 85%) to the average total clearance of 1.1-1.8 l/min. after intravenous administration. Renal excretion of fenoterol (0.27 L/min) corresponds to approximately 15% of the average total clearance of the systemically available dose. Considering the part of the drug that binds to plasma proteins, the renal clearance value indicates tubular secretion of fenoterol in addition to glomerular filtration.
After oral and IV administration, the total radioactivity excreted in urine is approximately 39% and 65% of the dose, and the total radioactivity excreted in feces is 40.2% and 14.8% of the dose over 48 hours, respectively. After oral administration, 0.38% of the dose is excreted unchanged into the urine, while with intravenous administration - 15%. After inhalation using a metered dose inhaler, 2% of the dose is excreted unchanged in the urine within 24 hours.
In unchanged form, fenoterol hydrobromide can cross the placental barrier and enter breast milk.
The metabolism of fenoterol hydrobromide in diabetes has not been sufficiently studied.
Use of the drug Berotek N
Attack of asthma. In most cases, 1 dose inhalation is sufficient to relieve an asthma attack; if after 5 minutes the effect is insufficient, inhalation can be repeated. If the attack does not resolve with two doses and there is a need for further inhalation, the patient should immediately seek medical help. Prevention of exercise-induced asthma: 1-2 doses per inhalation, but not more than 8 doses per day. Asthma and other conditions with reversible bronchial obstruction: 1–2 inhalations per dose, if repeated inhalations are necessary, but not more than 8 inhalations per day. Children should use Berotec N 100 mcg metered dose aerosol only as prescribed by a doctor under adult supervision.
Berotec® N
Doses for adults and adolescents over 12 years of age
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, one inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after two inhalations and additional inhalations are required, you should immediately seek medical help at the nearest hospital. Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations per day.
Doses for children from 6 to 12 years
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, one inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after two inhalations and additional inhalations are required, you should immediately seek medical help at the nearest hospital. Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations per day.
Doses for children from 4 to 6 years
Due to limited experience with children under 6 years of age, the drug should be used only as directed by a physician and under adult supervision.
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
To relieve bronchospasm, one inhalation dose is sufficient.
If there is no effect, you should immediately seek medical help at the nearest hospital.
Prevention of asthma by physical effort
1 inhalation dose before physical activity, up to 4 inhalations per day.
Mode of application
To achieve maximum effect, it is necessary to use a dosed aerosol correctly.
Before using metered dose aerosol for the first time, press the bottom of the can twice.
Each time you use a metered dose aerosol, the following rules must be observed:
1. Remove the protective cap.
2. Exhale slowly and completely.
3. Hold the can as shown in Fig. 1 and tightly wrap your lips around the tip. In this case, the arrow and the bottom of the inhaler are facing upward.
4. While inhaling as deeply as possible, simultaneously quickly press the bottom of the can until the inhalation dose is released. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly.
If repeated inhalation is required, repeat the same steps (steps 2-4).
5. Put on the protective cap.
6. If the aerosol can has not been used for more than three days, press the bottom of the can once before use.
The cylinder is designed for 200 inhalations. After this, the cylinder should be replaced. Although some drug may remain in the canister, the amount of drug released during inhalation may be reduced. The cylinder is opaque, so the amount of drug in the cylinder can only be determined in the following way: by removing the protective cap, the cylinder is immersed in a container filled with water. The amount of the drug is determined depending on the position of the cylinder in the water (see Fig. 2).
The inhaler should be washed at least once a week.
It is important to keep the mouthpiece of your inhaler clean so that medication does not accumulate and block the spray.
To clean, first remove the dust cap and remove the container from the inhaler. Rinse the inhaler with warm water to remove any accumulated medication and/or visible dust (see Figure 3).
After cleaning, shake the inhaler and allow it to air dry without using heating devices. When the mouthpiece is dry, return the container and dust cap to their place (see Fig. 4).
WARNING: The plastic mouthpiece is designed specifically for Berotek® N and is used for precise dosing of the drug. The mouthpiece should not be used with other metered dose aerosols. Also, Berotec® N should not be used with any adapters other than the mouthpiece supplied with the drug.
The contents of the cylinder are under pressure. The container must not be opened or heated above 50°C.
Side effects of the drug Berotec N
The most common side effects are skeletal muscle tremor, irritability, headache, dizziness, sinus tachycardia and palpitations. The possibility of developing severe hypokalemia cannot be excluded. As with the use of other inhaled agents, cough, local irritation, and paradoxical bronchospasm are possible. Berotec N, like other β-adrenergic agonists, can cause nausea, vomiting, hyperhidrosis, general weakness, myalgia, and muscle cramps. In some cases, especially after using the drug in high doses, a decrease in diastolic blood pressure, an increase in systolic blood pressure, and arrhythmia were noted. In case of hypersensitivity, allergic skin reactions were rarely observed. Psychiatric agitation has been reported in isolated cases during inhaled therapy with β-mimetics.
Special instructions for the use of the drug Berotek N
During pregnancy and breastfeeding. No negative effects have been identified when using the drug during pregnancy. However, special care must be taken when taking it in the first trimester of pregnancy. It is necessary to take into account the inhibitory effect of fenoterol on uterine contractility. Fenoterol passes into breast milk; The safety of using the drug during breastfeeding has not been established. The need for simultaneous anti-inflammatory therapy in patients with asthma and patients with steroid-dependent COPD should be considered. When using the new Berotec N metered-dose aerosol for the first time, some patients may note that its taste is slightly different from the previous aerosol containing freon. Patients should be informed about this when prescribing the new Berotec N metered dose aerosol, and also that both dosage forms of the aerosol are interchangeable and identical in their properties, and the difference in taste does not affect the effectiveness and safety of the drug. Concomitant use with other sympathomimetic bronchodilators should only be done under medical supervision. Anticholinergic bronchodilators can be used for inhalation simultaneously with Berotec N. In some situations, especially at doses higher than recommended, Berotec N should be used only after a careful assessment of the risk/benefit ratio. Such situations include poorly controlled diabetes mellitus, recent myocardial infarction, severe organic lesions of the heart or blood vessels, hyperthyroidism, and pheochromocytoma. In case of sudden development and rapid progression of shortness of breath, the patient should immediately consult a doctor. With long-term use of the drug, “as needed” administration is more preferable than regular use. The use of the drug does not exclude the simultaneous use of basic anti-inflammatory therapy (for example, inhaled corticosteroids) for asthma and COPD to prevent the progression of pathological changes in the lungs. With increasing bronchial obstruction, exceeding the recommended dose of a drug containing β2-agonists, such as Berotec N, may lead to further deterioration of the patient's condition. Use of β2-agonists such as Berotec N in high doses over a long period of time may lead to worse control of symptoms of bronchial obstruction. In this situation, to prevent a potentially life-threatening condition, it is necessary to review the treatment regimen and especially the adequacy of anti-inflammatory therapy. Severe hypokalemia may occur during therapy with β2-adrenergic agonists. Particular attention is necessary in severe forms of asthma, since in this case hypokalemia can be potentiated by the simultaneous administration of xanthine derivatives, corticosteroids, and diuretics. In addition, hypoxia as a symptom of asthma can enhance the negative effect of hypokalemia on heart rate. In such situations, monitoring serum potassium levels is recommended. Warning. The cylinder is designed for 200 inhalations. After using 200 doses, it must be replaced, even if it contains a residual amount of the drug. The plastic tip is specially designed for Berotek N metered aerosol and serves for precise dosing. The tip is not recommended for use with other metered aerosols. The inhalation tip should be kept clean and, if necessary, can be washed with warm water. After using soap or detergent, rinse the handpiece thoroughly with clean water.
Interactions of the drug Berotec N
β-adrenergic agonists, anticholinergics and xanthine derivatives (such as theophylline) may enhance the effects of fenoterol. Simultaneous administration of other β-adrenergic agonists, systematic use of anticholinergics and xanthine derivatives (for example, theophylline) may increase side effects. With simultaneous use of beta-adrenergic blockers, there is a potential for a serious reduction in bronchodilation. β-adrenergic agonists should be administered with caution to patients taking MAO inhibitors or tricyclic antidepressants, as the effects of β-adrenergic agents may be enhanced. Inhalation of halogenated hydrocarbon anesthetics (halothane, trichlorethylene, enflurane) can increase the severity of the effect of β-adrenergic drugs on the cardiovascular system.
Overdose of the drug Berotec N
Possible symptoms of overdose are excessive β-adrenergic stimulation, including tachycardia, palpitations, tremor, hypertension (arterial hypertension), hypotension, increased pulse blood pressure, angina pectoris, arrhythmia, and flushing. Treatment: sedatives, tranquilizers; β-adrenergic receptor blockers, preferably β1-selective, are used as specific antidotes. The possibility of increased bronchospasm should be taken into account, so patients with asthma must carefully set the dose.
Berotek N
Adults and teenagers over 12 years old
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, 1 inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after 2 inhalations and additional inhalations are required, you should immediately consult a doctor.
Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations/day.
Children from 6 to 12 years old
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
In most cases, 1 inhalation dose is sufficient to relieve bronchospasm; If breathing relief does not occur within 5 minutes, inhalation can be repeated.
If there is no effect after 2 inhalations and additional inhalations are required, you should immediately seek medical help.
Prevention of asthma by physical effort
1-2 inhalation doses before physical activity, up to 8 inhalations/day.
Children from 4 to 6 years old
Due to limited experience with children under 6 years of age, the drug should be used only as directed by a physician and under adult supervision.
Attacks of bronchial asthma and other conditions accompanied by reversible airway obstruction
To relieve bronchospasm, 1 inhalation dose is sufficient. If there is no effect, you should immediately seek medical help.
Prevention of asthma by physical effort
1 inhalation dose before physical activity, up to 4 inhalations/day.
Rules for using the drug
To achieve maximum effect, it is necessary to use a dosed aerosol correctly.
Before using the metered-dose aerosol for the first time, press the bottom of the can twice.
Each time you use a metered dose aerosol, the following rules must be observed.
1. Remove the protective cap.
2. Take a slow, deep breath.
3. Hold the can and tightly wrap your lips around the tip. In this case, the arrow and the bottom of the can must be directed upward.
4. Inhaling as deeply as possible, simultaneously quickly press the bottom of the can until 1 inhalation dose is released. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly. If repeated inhalation is required, repeat the same steps (steps 2-4).
5. Put on the protective cap.
6. If the aerosol can has not been used for more than 3 days, you should press the bottom of the can once before use.
The cylinder is designed for 200 inhalations. Then the cylinder should be replaced. Although some contents may remain in the canister, the amount of drug released during inhalation is reduced.
The cylinder is opaque, so the amount of drug in the cylinder can be determined as follows: remove the protective cap, immerse the cylinder in a container filled with water. The amount of the drug is determined depending on the position of the cylinder in the water.
rice. 1.
The inhaler should be washed at least once a week.
It is important to keep the mouthpiece of the inhaler clean so that medication does not accumulate and block the spray.
To clean, first remove the dust cap and remove the container from the inhaler. Rinse the inhaler with warm water to remove any accumulated medication and/or visible dust.
After cleaning, you need to shake the inhaler and let it air dry without using heating devices. When the mouthpiece is dry, return the container and dust cap to their place.
The plastic mouthpiece is designed specifically for the Berotec® N metered aerosol and serves for precise dosing of the drug. The mouthpiece should not be used with other metered dose aerosols. Berotec® N metered dose aerosol cannot also be used with other adapters.
Overdose
Symptoms: tachycardia, increased heart rate, tremor, decreased/increased blood pressure, increased pulse pressure, anginal pain, arrhythmias, facial flushing, metabolic acidosis.
Treatment: prescription of sedatives, tranquilizers; in severe cases, intensive symptomatic therapy is indicated.
The use of beta-blockers (preferably selective beta1-blockers) is recommended as specific antidotes. However, it is necessary to take into account the possibility of increased bronchial obstruction and carefully select the dose of these drugs in patients with bronchial asthma.
