New opportunities in the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is currently one of the most common diseases of the bronchopulmonary system, which, especially in the absence of adequate treatment, causes severe disability and premature death.

COPD is a disease characterized by progressive bronchial obstruction, which is only partially reversible. The pathophysiological basis of impaired bronchial patency is the inflammatory “response” of the lungs to inhalation exposure of damaging particles or gases.

As a result of prolonged inhalation exposure of irritants (tobacco smoke components, sulfur dioxide, nitrogen, ozone, etc.), predisposed individuals develop consistent and closely interconnected pathological processes in the wall of the bronchi (hyperplasia of the mucous-forming elements, disturbance of the bronchial secretion rheology) and in the lung tissue (elastolitic destruction), leading to the formation of chronic bronchitis and emphysema – the main components of COPD. It is advisable to allocate an irreversible and reversible bronchial obstruction, thereby predicting the possibilities and limitations of the available drug therapy for this disease.

The irreversible (“emphysematous”) component of bronchial obstruction is due to the development and progression of emphysema and so-called. diseases of the small bronchi (reduction of the elastic tension of the lung tissue due to uneven predominantly centriacinal emphysema, early expiratory collapse, deformity and narrowing of the small bronchi). It is obvious that these structural changes cannot be the point of application of bronchodilators and/or anti-inflammatory drugs.

The reversible (“bronchitis”) component of bronchial obstruction is represented by inflammatory edema of the respiratory tract mucosa, accumulation of inflammatory cells, mucus and plasma in the lumen of the bronchi, spasm of smooth muscles. At the same time, swelling of the mucous membrane of the respiratory tract, hyperplasia of the submucous glands and goblet cells, hyperproduction of mucus, combined by the term “inflammatory remodeling of the bronchial wall”, is controlled by the parasympathetic division of the autonomic nervous system, the tone of which in this disease is naturally increased. And since cholinergic innervation is the dominant neurogenic mechanism of bronchoconstriction, it is obvious that anticholinergic drugs should be considered as a priority for bronchodilator therapy of COPD.

The parasympathetic nervous system plays an important role in the development of bronchoconstriction in humans. Cholinergic preganglionic fibers originate from the nucleus ambiguus and dorsal motor nuclei in the brain stem and in the vagus nerve reach the peripheral parasympathetic ganglia located in the bronchial wall, and then short postganglionic fibers reach the smooth muscle cells of the bronchi and submucous glands. Stimulation of vagus, in particular, with inflammatory mediators (bradykinin) leads to the release of acetylcholine, which activates the muscarinic receptors of smooth muscle cells, submucous glands and goblet cells of the airways, causing bronchoconstriction and hypersecretion of mucus. Cholinergic innervation is most common at the level of the large bronchi and to a lesser extent at the level of the peripheral bronchi.

Bronchodilator therapy may be prescribed “on demand” or on a regular basis. But since the main goals of treating patients with COPD are to reduce the rate of progression of diffuse inflammation, leading to an increase in bronchial obstruction, development and worsening of respiratory failure, reducing the frequency and duration of exacerbations, improving quality of life, it is obvious that long-term and regular treatment has priority.

Anticholinergic drugs (or M-cholinolytics), which are competitive acetylcholine antagonists, block the muscarinic receptors and thereby eliminate the effects of parasympathicotonia on the postsynaptic smooth muscle receptors and mucus-forming elements of the bronchi. Currently inhaled anticholinergic drugs are quaternary ammonium derivatives, and the most widely distributed ipratropium bromide (IB). The drug is well tolerated, effective and safe with prolonged use, does not cause the development of tachyphylaxis, cardiotoxic action. The sensitivity of the M – cholinergic receptors does not decrease with age, which is especially important in the treatment of patients with COPD, since this disease is typical for people of the older age groups. Existing recommendations suggest applying IB “… for as long as the symptoms of the disease continue to cause inconvenience to the patient”.

A representative of the generation of anticholinergic drugs is tiotropium bromide (TB), also referring to quaternary ammonium derivatives. TB interacts with all types of muscarinic receptors. However, in an in vitro study (on isolated guinea pig lungs and the human respiratory tract), it was shown that TB dissociates with M1– and M3 receptors 100 times slower than IB, and, on the contrary, very quickly with M2 receptors. This circumstance determines the unique kinetic selectivity of the drug in relation to the M3– and M1 – receptors and minimal interaction with the M2 – receptors. The slow dissociation of TB with M3 receptors of smooth muscle cells and mucus-forming elements of the respiratory tract explains the significant duration of the drug’s action, which makes it possible to use it once a day. The duration of the bronchodilator effect is dose-dependent and, for example, during inhalation of 40 μg of the drug reaches 48 hours. It was also found that the anticholinergic effect of TB is approximately 10 times greater than that of IB.

The leading direction of planned long-term therapy for COPD is the administration of inhaled anticholinergic drugs or M-cholinolytics (ipratropium bromide – IB). Among the most promising representatives of the new generation of anticholinergic drugs is tiotropium bromide (TB). Slow dissociation of TB from M3– or postsynaptic cholinergic receptors of smooth muscle cells and respiratory mucosa elements explains the possibility of effective use of the drug 1 time per day compared with the need for 3-4 times the use of IB. At the same time, the holinoblocking effect of TB is approximately 10 times greater than that of IB. TB is prescribed in a dose of 18 µg / day once in the form of a metered-dose powder inhaler.

Numerous controlled clinical studies assessing the efficacy and safety of TB during its 12-month intake confirmed the significant superiority of the drug in comparison with placebo and IB in influencing the indices of bronchial patency, the “situational” need for short-acting bronchodilators, dyspnea severity, frequency and severity of exacerbations diseases, indicators of quality of life. Of fundamental importance is the property of TB to slow down the rate of progressive decline in bronchial patency.

A single dose of TB per day, combined with a good effect and an attractive safety profile, explain the high compliance (more than 90%), demonstrated by the absolute majority of COPD patients during long-term administration of the drug.

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