Inhalation therapy of bronchoobstructive syndrome
This article provides an overview of the main groups of drugs used for the treatment of undifferentiated bronchialobstruction, highlight the indications and contraindications for the use of different groups bronhodilaters. Displaying priority use the inhalation route for administration of drugs. Treatment of undifferentiated bronchial obstruction syndrome (BOS) consists of a therapy that causes bronchodilation and improves the drainage bronchial function. Smooth muscular tonus is regulated by stimulation of α-adrenergic, β- adrenergic and M-cholinergic, H <sub>1</sub>-histaminergic and 5-hydroxytripthaminic receptors. Excitation of α-adrenergic receptors leads to bronchospasm, and β <sub>2</sub>-adrenergic stimulation - bronchodilation. Well-known, there are three main groups of bronchodilators:β2-agonists(sympathomimetic), M-anticholinergics, methylxanthines. Moderate bronchodilation also provide calcium antagonists, α-blockers, myotropic spasmolitics and prostaglandin E group [14]. Universal sympathomimetic distinguish - stimulating α, β1, β2-adrenergic receptors (adrenaline, ephedrine), non-selective sympathomimetics cooperate on the β1, β2-receptors (isoprenaline hydrochloride, orciprenale sulfate) and selective β2- agonists (salbutamol, fenoterol, terbutaline). The pharmacological effects of this drug-mediated stimulation of β2-adrenergic receptors in the bronchial tubes, the density of which increases with reduction in bronchial diameter, as well as through the stimulation of β2-adrenergic receptors on the surface of mast cells, lymphocytes, eosinophils, and others [1, 5]. Selective β2-agonists have the following therapeutic effects: relaxation of smooth muscles throughout the bronchial of the tree, the activation of the mucociliary clearance due to the involvement in the bronchial lumen of chloride ions and water, inhibition of secretion of goblet cells, reducing permeability and edema of the bronchial mucosa, increasing of diaphragm contractility [13]. For bronchodilation following methods of introducing drugs are used: inhaled, oral and parenteral (subcutaneous, intramuscular, intravenous). Epinephrine (adrenaline) is inactivated in the stomach after oral using completely. Ephedrine, hexoprenaline, orciprenaline, terbutaline, salbutamol, fenoterol, clenbuterol are absorbed from the gastrointestinal tract. Epinephrine, ephedrine, orciprenaline, terbutaline, salbutamol can also be administered parenterally [16]. However, the most efficient way of introduction - inhalation, which provides bronchodilation faster at lower doses. β2- agonists after oral administration under intense first-pass metabolism of the first pass through the liver, so the bioavailability of orally forms of β2- agonists is very low. When inhaled route of administration of the dose, for various reasons not reach the bronchial tubes (adsorbed in the cavity of the mouth or airways leaves exhaled air). Dumping metered aerosol to the lungs gets only 5-15 % of the dose inhaled dry powder - up to 30-38 %, while using a nebulizer - 50-70 %. The main advantage of inhalation therapy is the delivery of a medications directly into the airways, which allows dosе evolve a high local concentrations of the drug and reduce the risk of systemic side effects, makes it possible to accelerate the positive effect of the treatment at the expense of smaller doses of drugs [12]. Inhalations of terbutaline, salbutamol have a rapid bronchodilating effect lasting up to 4-6 hours and 7-8 hours - for the fenoterol. Formoterol and salmeterol have longest bronchodilator activity (12 hour), the differences in speed of onset of effect: formoterol acts quickly, salmeterol - more slowly (30 min). Parenteral administration of β2-agonists uses in acute severe asthma, COPD, accompanied by severe edema of the mucosa and hypersecretion of viscous mucus, as expressed by airway obstruction prevents the penetration of aerosol in the bronchial tubes [9]. In the treatment of bronchial asthma (BA), COPD short-acting β2- agonists are used for emergency care of the breathlessness. These preparations should not be used for the basic therapy, as they do not possess antiinflammatory and prolonged bronchodilating action. Controlled asthma is determined when the attacks of dyspnea develop less than 2 times per week. If the patient uses a short-acting bronchodilators more frequently, 3-4 times per day, this is a measure of the flow of uncontrolled asthma, the development of exacerbation of the disease in a patient [3, 10, 18]. Abuse of drugs in this group may lead to a threat capable of damaging living states: rebound syndrome and "lock-syndrome". Syndrome diagnosed by a ricochet when each of the following attacks are more severe than the previous one, or sympathomimetic completely is ineffective and use worsens the condition of patients. The rebound syndrome is the accumulation of metabolic products of agonists that induces β-receptor blockade and reduction of their number on the surface of cells, their partial degradation. The rebound syndrome is characterized by gradual increasing of dyspnoe with short-term improvement in breathing after inhalation, worsening of sputum expectoration due to expansion of bronchial submucosal vessels in violation of their drainage function, which contributes to swelling of the bronchial tubes and the deterioration of bronchial obstruction. Therefore, time to time inhalable drugs is necessary to change for the prevention of these conditions or connect to the treatment with small doses of non-selective sympathomimetic agents (epinephrine, ephedrine), which have anti-and vasoconstrictor effect by stimulation of α- adrenergic receptors [2, 19]. Among the side effects of SAB should be made an impact on the cardiac- vascular system: tachycardia, elevated blood pressure, hypokalemia. There are in rare cases nausea, vomiting, constipation, destruction of ciliated epithelial cells of the bronchial mucosa. Hypoxemia significantly increases the risk of adverse events SAB. When using a sympathomimetic main mechanism of hypoxemic increasing is β <sub>2</sub>- induced pulmonary vasodilation, which leads to further deterioration of the ventilation-perfusion ratio and the rise of hypoxemia. As a result the risk of myocardial ischemia and arrhythmias associated with the using of SAB elevates. This adverse effect is noteworthy in patients with PaO <sub>2</sub> less than 60 mm Hg, so inhalation therapy should be carefully monitored blood oxygen saturation. Selective SAB, early treatment can cause muscle tremors [4, 19]. Side effects of fenoterol and salbutamol (tachycardia, hypoxemia and hypokalemia) are usually manifested as after 20-40 breaths of 100 mcg via metered dose inhaler [11]. Contraindications to SAB are: hypersensitivity; Ischemic heart disease; hypertension; hyperthyroidism. And to select the optimal bronchodilator should be remembered that in the regulation of muscle tone of the bronchi involved as sympathetic and parasympathetic autonomic nervous system. Parasympathetic autonomic nervous system plays an important role in the development of bronchoconstriction in humans. Sympathetic nervous system causes bronchodilation and reduced bronchial hypersecretion. Both systems operate synergistically [6]. In the pathogenesis of bronchoconstriction increasing of vagal tonus has a definite value, as its stimulation causes the release of acetylcholine which activates muscarinic receptors of smooth muscle cells, sub- mucosal glands and goblet cells of the respiratory tract, causing bronchial constriction and mucus hypersecretion. The cholinergic innervation of the spreads at large bronchi, and to a lesser extent - on the level of peripheral bronchi. Anticholinergic drugs by blocking muscarinic receptors, counteract the effect of acetylcholine on receptors in bronchial smooth muscle and glands of the bronchi. In the application of anticholinergics bronchial tonus reduces through the relaxation of smooth muscle, decreases the severity of bronchial obstruction and bronchial hypersecretion of mucus glands and goblet cells, reduces cough, sputum, dyspnea [12]. "Classic" M- anticholinergic - atropine (in the middle of the 19 th century, was as the "gold standard" in the treatment of asthma, now does not use due to severe side effects (dry mouth, mydriasis, the penetration of human hematoencephalic barrier, etc.). Quaternary derivatives - troventolum, ipratropium bromide, oxitropium, tiotropium - very similar in pharmacological properties, but do not have the undesirable systemic effects, are highly active by inhalation use. Action of ipratropium bromide starts after 20-40 min, reaches a maximum at 1 hour, continues 5-6 hours, while a more pronounced bronchodilator action is at the proximal bronchi. The benefits of inhaled anticholinergics (ACE) is also something that does not develop tachyphylaxis during long-term use. In patients with concomitant cardiovascular disease M-anticholinergics may be an alternative SAB due to their use does not cause tachycardia, and cardiac output change. Number of adverse cardiovascular effects after use of two standard doses of β <sub>2</sub>- agonist, compared with 30 standard doses of ipratropium. Contraindications to ACE: hypersensitivity to its components. Side effects: dry and bitter taste in the mouth, pain in the throat or chest, cough, allergic reactions, paradoxical bronchospasm (3 % of patients). This low potential side effects can successfully use it in the elderly. Improving effect on bronchial wall leads to the combined use of two drugs in the same inhaler, thus complement each other as the influence on airway receptors, and the topography of the location of these receptors and the rate of occurrence of effects. The idea of creating a combined bronchodilator, two components of which the first action would be exerted on the various mechanisms of bronchial obstruction, turned out to be successful and Berodual more than a quarter century, is widely used in many countries as an effective bronchodilator. Berodual H - combined drug with strong bronchodilator effect caused by fenoterol (50 mcg) and ipratropium bromide (21 mcg). The components of the drug have different applications. Adding the ACE to SAB increases their bronchodilation effect. Both active ingredients Berodual H relax the smooth muscles of the bronchi by acting on different targets, resulting in their bronchodilation - parameter effect is enhanced. The combination of complementary components that enable you to get a pronounced effect of bronchodilators using less than half fenoterol dose (50 micrograms), which reduces to a minimum the chance of unwanted effects, including during concomitant cardiac pathology [16]. Thus, the undoubted advantages of Berodual H are: combination of β <sub>2</sub>-stimulating and anticholinergic effects, makes it possible to eliminate airflow obstruction at all levels of the bronchial tree; different duration (more rapid onset - the β <sub>2</sub>-agonist, a more prolonged action - the anticholinergic drugs); minimal side effects (a lower dose of each ingredients in combination compared with monotherapy dose preparation to achieve the same effect of bronchodilation); greater security in combination with concomitant cardiac disease than monotherapy of β <sub>2</sub>- agonists; the drug of choice in the treatment of asthma, accompanied by a pronounced increase in parasympathetic tonus of the autonomic nervous system; saving efficiency during prolonged use; various forms of delivery metered dose inhaler and a nebulizer solution.