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Tiotropium bromide is a new long-acting anticholinergic drug

Iotropium bromide (TB) is a quaternary ammonium compound similar in chemical structure to ipratropium bromide. Both drugs are practically not absorbed through the mucous membrane of the oropharynx and respiratory tract and are characterized by insignificant oral bioavailability, which explains the absence or minimal frequency and severity of systemic anticholinergic effects when used by inhalation [1,2].

Non-selective anticholinergic drugs - atropine, ipratropium bromide and oxytropium bromide - are known to interact with all three types of muscarinic receptors. Moreover, if blockade of M1 and M3 receptors leads to bronchodilation, then blockade of M2 receptors, accompanied by increased release of acetylcholine into the synaptic cleft, can to some extent reduce the beneficial effects of blockade of postsynaptic M3 receptors. From a theoretical point of view, the use of a selective M3 receptor blocker seems optimal, but to date it has not been possible to create such a drug [3].

TB has unique kinetic selectivity with a predominant effect on M1 and M3 receptors [1,4,5]. The drug demonstrates a comparatively high degree of affinity for all types of muscarinic receptors, however, the dissociation of the drug with M1 and especially M3 receptors is significantly slowed down, which causes a prolonged blockade of cholinergic bronchoconstriction. On the contrary, the dissociation of TB with M2 receptors is significantly faster (Table 1), which suggests the so-called kinetic selectivity of the drug [6,7].

Like other bronchodilators,
TB is characterized by the following sanogenetic effects:

Bronchodilation
- relaxation of the tone of the smooth muscle cells of the airways - is characterized by an increase in forced expiratory volume in 1 second (FEV1), but in patients with COPD the dynamics of this indicator are often minimal (<10% of the expected values).
A decrease in dynamic hyperinflation
, accompanied by a decrease in residual volume and functional residual capacity of the lungs, which explains the patient’s symptomatic improvement: the severity of shortness of breath decreases, breathing becomes more “comfortable” [8,9].
Symptomatic improvement is often more pronounced
in comparison with the minimum dynamics of FEV1, especially in patients with moderate to severe COPD [10,11].
An increase in exercise tolerance
is one of the most noticeable therapeutic effects when using bronchodilators in patients with COPD [12].
Increased mucociliary clearance
[13].

Unfortunately, to date there is no direct evidence that bronchodilators are able to modify the natural course of COPD, i.e. slow down the rate of decline in bronchial patency indicators (FEV1) [14].

The duration of the bronchodilator effect of TB exceeds 24 hours. After inhalation of 10 mcg of TB, rapid absorption is observed within the next 5 minutes, reaching a peak plasma concentration of 6 pg/ml; over the next hour, a steady state is established with a plasma concentration of 2 pg/ml, and the terminal half-life is 5–6 days (regardless of the dose taken) [4]. It is estimated that the amount of drug taken “occupies” less than 5% of muscarinic receptors, which partly explains the almost complete absence of systemic adverse events. There is no evidence that TB accumulates with repeated use. In the therapeutic dose range (intravenous administration, powder inhalation), TB is characterized by linear pharmacokinetics [13].

The pharmacokinetics of TB have been well studied in both experimental and clinical settings [15]:

Absorption

. After inhalation of TB in the form of a dry powder, the absolute bioavailability of the drug is 19.5%, indicating that the pulmonary fraction of the drug is characterized by high bioavailability. On the contrary, since TB is a quaternary ammonium compound, it is characterized by extremely low gastrointestinal absorption (10–15%).

Distribution

. 72% of TB are bound to plasma proteins and the volume of distribution is 32 L/kg. 5 minutes after inhalation of 18 μg of TB by patients with COPD, the peak plasma concentration of TB reaches 17–19 pc/ml, and the equilibrium plasma concentration is 3–4 pg/ml.

Metabolism

. The degree of biotransformation of TB is insignificant - in studies on young healthy volunteers after intravenous administration, 74% of the drug is excreted unchanged in the urine.

To date, extensive experience has been accumulated in assessing the effectiveness and safety of TB in the treatment of patients with COPD.

Single-dose TB studies

In a study assessing the spirometric effects and safety of a single dose of TB in patients with COPD, nebulization of the solution was carried out in a dose range from 10 to 160 μg of the drug. The long-lasting bronchodilator effect of TB (>24 hours) and the absence of significant adverse events were confirmed [3]. In another study, TB was administered in a dose range from 10 to 80 mcg (in the form of a metered dose powder inhaler - DPI) and a clear dose-dependent effect of the drug was confirmed [16].

7-day TB studies

The study demonstrated that about 70% of the bronchodilator effect achieved after using TB is observed after taking the first two doses of the drug, and the equilibrium state of FEV1 is achieved within the next 48 hours [17].

4-week TB studies

During a 4-week administration of TB (once daily, in the dose range from 4.5 to 36.0 mcg), when assessing the dynamics of FEV1, a flat dose-effect curve was established. Based on these data, for long-term use of TB, the choice was made in favor of 18 mcg of the drug (1 time/day), since a dose of 36 mcg was characterized by a clear increase in the frequency of such an adverse event as dry mouth, in the absence of a significant increase in FEV1 [18].

13-week TB studies

When TB was prescribed at a dose of 18 mcg 1 time/day in the form of DPI “Handihaler” for 13 weeks, it was shown that the use of TB was more effective than monotherapy with IB, prescribed 4 times/day [19].

In a study conducted by members of The US Tiotropium Study Group

, 13-week administration of TB in patients with COPD was compared with administration of placebo: the anticholinergic drug demonstrated significant superiority in its effect on bronchial obstruction parameters (FEV1, peak expiratory flow rate), disease symptoms, use of short-acting b2-agonists “on demand”, etc. [20 ].

12-month TB studies

Long-term continuous use of TB in patients with moderate/severe COPD was accompanied by a significant improvement in bronchial obstruction, regression of clinical symptoms, optimization of quality of life indicators and a decrease in the frequency of exacerbations of the disease [10,11]. These studies demonstrated that the effect initially observed in the 4- and 13-week studies extended over a significantly longer period of time, indicating no development of tolerance (tachyphylaxis) for at least 12 months.

In particular, the effect of long-term use of TB on the frequency of exacerbations of COPD is indicative: taking the drug was accompanied by the development of an exacerbation within a year in less than half of the observed patients, and only every 10th patient was hospitalized.

TB compared with salmeterol (6-month use)

During six-month administration of TB or salmeterol in patients with COPD, the superiority of TB in the severity of bronchodilation, regression of shortness of breath, and optimization of quality of life indicators was demonstrated [21].

In addition to these now classic studies, works have recently been published that expand our understanding of TB in the treatment of patients with COPD.

The purpose of one study was to prove the possibility of long-term symptomatic improvement in patients with COPD during long-term maintenance therapy for TB, despite the absence or insignificant increase in FEV1 against the background of previous short-term use of bronchodilators [22]. The authors analyzed the results of two 12-month studies that compared the effectiveness of tiotropium (18 mcg/day) and placebo in influencing long-term improvements in functional parameters and health status of patients depending on the results of the bronchodilator test performed on the first day of the study (it was considered positive with dynamics of FEV1 >= 12% or >= 200 ml). All patients receiving TB were divided into two groups: a) positive test – TB – “ responders”

"(i.e. those who responded);
b) negative test – TB – “ non responders
” (i.e. those who responded poorly).
A year later, in both groups, FEV1 values (in the morning, before the next TB inhalation) increased by 212±17 ml and 94±17 ml, respectively (compared to placebo). The same applied to the severity of shortness of breath and quality of life assessment according to the SGRQ (St. George's Respiratory Questionnaire): –3.96±0.99 and –3.05±1.00 points, respectively, compared to placebo. At the same time, a weak correlation between the results of the bronchodilator test on the first day of the study and the subsequent dynamics of the dyspnea index and the integral score of quality of life according to the SGRQ questionnaire was confirmed. Thus, TB demonstrates high effectiveness regardless of the results of the bronchodilator test
, so the latter cannot be used as a predictor of the effectiveness of long-term therapy.

During two 6-month placebo-controlled comparative studies of the effectiveness of TB (18 mcg once a day, Handihaler DPI) and salmeterol (50 mcg twice a day, MDI), the dynamics of the frequency of exacerbations, the severity of shortness of breath, and the integral indicator of quality of life were assessed (SGRQ) and spirometry indicators [23]. A total of 1207 patients were included in the studies (TB - 402, salmeterol - 405, placebo - 400). The lowest number of exacerbations of COPD (patient/year) was in the group of patients taking TB - 1.07 compared with placebo - 1.49 (<0.05) and salmeterol - 1.23. The mechanism for reducing the frequency of exacerbations of COPD during long-term bronchodilator therapy remains incompletely understood. As is known, the leading clinical manifestation of COPD is dyspnea that progresses in intensity, which, as a rule, is a consequence of the increase in hyperinflation during an exacerbation of COPD. Bronchodilators (b2-agonists, anticholinergic drugs) increase the FEV1 value, but FVC is also optimized, which ultimately can lead to a decrease in hyperinflation. Such an improvement in ventilation parameters is accompanied by a decrease in the severity of shortness of breath, especially when performing physical activity. The result of the study - TB, in comparison with placebo, demonstrates a clear decrease in the severity of shortness of breath, improvement in bronchial obstruction, a decrease in the frequency of exacerbations and an improvement in the quality of life of patients

. When taking salmeterol compared to placebo, such effects are less pronounced, unreliable and insignificant from a clinical point of view.

It is generally accepted that COPD is a disease characterized by progressive bronchial obstruction, which is only partially reversible [24]. At the same time, not a single therapeutic effect is capable of “interfering” with the natural course of the disease, i.e. to slow down the rate of annual decline in FEV1 to any significant extent. At the same time, somewhat encouraging data have recently emerged - we are talking about the beneficial consequences of long-term use of TB in patients with COPD. Thus, in one of the placebo-controlled studies assessing the effectiveness of 12-month TB treatment, it was shown that in the group of patients taking placebo (n = 328), the decrease in FEV1 over the specified time period averaged 58.0 ml, and in to the group of patients taking a bronchodilator (n=518) – only 12.4 ml (p<0.005) [25].

So, in the course of numerous controlled studies, it was possible to prove the superiority of TB compared to placebo, ipratropium bromide and salmeterol in influencing individual clinical manifestations, spirometric parameters, indicators of the quality of life of patients with COPD, etc. (Table 2).

Adverse events (AEs) of TB, like any other anticholinergic drug, are pharmacologically predictable and dose-dependent. The inhalation route of delivery of anticholinergic drugs determines the minimum frequency and severity of systemic AEs. However, the majority of COPD patients are older people, often suffering from concomitant diseases. Hence, obviously, the risk of developing AEs from drug therapy increases. The extreme rarity of AEs when taking TB is explained by the inhalation route of administration and the virtual absence of systemic absorption of the drug. Numerous studies have proven that inhaled anticholinergic drugs are extremely safe medications. The most common AEs when using anticholinergic drugs [13]:

1) Dry mouth and cough are the most common AEs observed with the use of TB in 15% of patients (a similar frequency of these AEs was noted with the use of ipratropium bromide) [19].

2) Pharyngitis, upper respiratory tract infections.

3) Bitter metallic taste in the mouth (noted by some patients).

4) Paradoxical bronchoconstriction (possible with nebulization of ipratropium solution).

5) Immediate hypersensitivity reactions (rare).

6) An increase in intraocular pressure can be observed in elderly patients when using a face mask solution during nebulization (associated with the direct effect of the drug on the eye).

7) Systemic AEs are extremely rare: urinary retention, constipation, tachycardia, palpitations.

Headache, increased excitability, irritability, dizziness.

It is important to note that when anticholinergic drugs are used, mucociliary clearance remains intact, although bronchial mucus secretion may be reduced. Anticholinergic drugs do not have a significant effect on the tone of the pulmonary vessels and therefore, unlike b2-agonists and theophylline, do not lead to a drop in the partial oxygen tension in the arterial blood.

In the following clinical situations, anticholinergic drugs (including TB) should be used with caution:

A) Dryness of the oral mucosa, which is often observed in patients suffering from caries.

B) Conjunctivitis.

C) Benign prostatic hyperplasia, urinary retention, urinary disorders associated with bladder dysfunction.

D) Heart rhythm disturbances.

E) Patients with renal and liver failure can use TB in recommended doses, although there is no experience with long-term use of the drug in these categories of patients.

The developer and manufacturer of TB – – entered into a marketing agreement with the promotion of TB under the trade name “ Spiriva”

» in all countries at the same time (including the Russian Federation). TB comes in the form of a single-dose powder inhaler called Handihaler. Each capsule contains 22.5 mcg tiotropium bromide monohydrate, equivalent to 18 mcg tiotropium. The dose of TB released by inhalation of Handihaler is 10 µg [26]. As with any other device, for inhalation therapy, effective use of the discussed DPI requires the patient to have perfect inhalation maneuver technique. Since the majority of patients with COPD are older people, the use of a MDI causes certain difficulties for them, which requires clear coordination of inhalation and actuation of the aerosol generator. On the contrary, DPIs have certain advantages in this category of patients due to their ease of use. When using Handihaler, to evacuate the contents of the capsule, a low inspiratory volumetric flow rate (IVR) is required, which even patients with severe COPD can develop (to carry out a full inhalation maneuver and evacuate the contents of the capsule, an ISV of 20 l/min is sufficient). For comparison, when using the Turbuhaler multi-dose powder inhaler, it is necessary to develop an TWS of 60 l/min [13].

The TB dosing regimen is simple and convenient - the drug is prescribed at a dose of 18 mcg in the form of DPI once a day, usually in the morning or at noon. This property of the drug explains the high adherence of patients to medical recommendations: during a 12-month observation, compliance of more than 90% is demonstrated by 85% of COPD patients (regardless of gender, age and severity of bronchial obstruction) [27], which significantly exceeds the frequency of satisfactory or good compliance in cases long-term use of IB and β-agonists (~60%) [28].

Conclusion

TB is a long-acting (>24 hours) anticholinergic drug given once daily. It has been shown that such a long-lasting effect of the drug is due to its slow dissociation with postsynaptic (effector) muscarinic (M3) receptors. TB is characterized by unique kinetic selectivity, consisting of slow dissociation with M1 and M3 receptors and, conversely, faster dissociation with M2 receptors, and demonstrates the selectivity of action that is so desirable in the treatment of patients with obstructive pulmonary diseases. Clinical studies assessing the effectiveness of TB in patients with COPD demonstrated a stable improvement in bronchial obstruction and the achievement of symptomatic control, exceeding the “consequences” of currently traditionally used IB.

TB is well tolerated; Dry mouth is the most commonly reported symptom (about 10%), but this AE is of little clinical significance.

Pharmacologists are naturally interested in the unique kinetic selectivity of the action of TB

.
From a theoretical point of view, this property may explain a certain attractiveness in the treatment of chronic obstructive pulmonary diseases, since it eliminates the increase in acetylcholine production, and therefore counteracts the final effect of the drug. However, it is unlikely that this property of TB is of particular clinical significance. Obviously, the most important property of TB is long-term bronchodilation and bronchoprotection (>24 hours). This property makes it possible to use the drug once a day, which is extremely important from a clinical point of view, since it ensures higher compliance. Another beneficial consequence of the long-term effect of the drug is the fact that periodic omissions of the next dose will not have a negative impact on the achieved control over the course of the disease, since the anticholinergic activity of the drug persists for more than 24 hours. Clinical studies have shown that TB prescribed once provides better control over the course of the disease. course of COPD
, rather than the modern standard of anticholinergic therapy - ipratropium bromide, used 4 times a day. It has also been shown that maximum bronchodilation can be achieved with relatively small doses of TB.

Overall, TB is seen as a very promising drug with a promising future. Since bronchodilators are the main class of drugs that have proven their effectiveness in long-term use by patients with COPD, TB can become the drug of choice for a large number of patients with moderate/severe (extremely severe) disease (Tables 3, 4).

Active research is currently underway to create new drugs that can interrupt the progression of COPD, but to date there is not a single drug that has this property.
For practical medicine, this means that TB will gain a stable position as a “leader” in bronchodilator therapy for COPD for many years. References:
1. Barnes PJ Tiotropium bromide. Expert Opin Investig Drugs 2001; 10: 733–740.

2. Hvizdos KM, Goa KL Tiotropium bromide. Drugs 2002; 62:1195–1203.

3. Maesen FPV, Smeets JJ, Costongs Ma AL et al. Ba 679 Br, a new long-acting antimuscarinic bronchodilator: A pilot dose-escalation study in COPD. Eur Respir J 1993; 6:1031–1036.

4. Disse B., Speck GA, Rominger KL et al. Tiotropium (Spiriva) mechanistic considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64:457–464.

5. Barnes PJ The pharmacological properties of tiotropium. Chest 2000; 117 (2 Suppl.): 63–68.

6. Disse B., Reichi R., Speck G. et al. A novel long-acting anticholinergic bronchodilator. Life Sci 1993; 52:537–544.

7. Haddad EB, Mak JC, Barnes PJ et al. Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: Radioligand binding and autoradiographic mapping. Mol Pharmacol 1994; 45:899–907.

8. Nisar M, Earis JE, Pearson MG et al. Acute bronchodilator trials in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 146:555–559.

9. O'Donnel DE, Lam M., Webb KA Measurement of symptoms, lung hyperinflation, m and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:1557–1565.

10. Casaburi R., Mahler DA, Jones PW et al. A long–term evaluation of once–daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002; 19: 217–224.

11. Vincken W., van Noord JA, Greethorst AP et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiptropium. Eur Respir J 2002; 19: 209–216.

12. Belman MJ, Botnick WC, Shin JW Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:967–975.

13. Hansel TT, Barnes PJ Tiotropium bromide: a novel once–daily anticholinergic bronchodilator for the treatment of COPD. Drugs of Today 2002; 38:585–600.

14. Anthonisen NR, Connett JE, Kiley JP et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497–1505.

15. Leusch A., Eichhorn B., Muller G. et al. Pharmacokinetics and tissue distribution of the anticholinergics tiotropium and ipratropium in the rat and dog. Biopharm Drug Dispos 2001; 22: 199–212.

16. Maesen FPV, Smeets JJ, Sledsens TJH et al. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator. A pharmacodynamic study in patients with chronic obstructive pulmonary disease. Eur Respir J 1995; 8:1506–1513.

17. van Noord JA, Smeets JJ, Custers FL et al. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 2002; 19: 639–644.

18. Littner MR, Ilowite JS, Tashkin DP et al. Long–acting bronchodilation with once–daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1136–1142.

19. van Noord JA, Bantje TA, Eland ME et al. A randomized controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000; 55:289–294.

20. Casaburi R., Serby W., Menjoge SS et al. The spirometric efficacy of once daily dosing with tiotropium in stable COPD. Am J Respir Crit Care Med 1999; 159:A524 (Abst.).

21. Donohue JF, van Noord JA, Babeman ED et al. A 6–month, placebo–controlled comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002; 122:47–55.

22. Tashkin D., Kesten S. Long–term treatment benefits with tiotropium in COPD patients with and without short–term bronchodilator responses. Chest 2003;123:1441–1449.

23. Busasco V., Hodder R., Miravitlles M. et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients

with COPD. Thorax, 2003; 58:399–404.

24. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Executive summary. Updated 2003 (www.goldcopd.com)

25. Anzueto A., Menjoge SS, Kesten S. Changes in FEV1 over time in 1-year clinical trials of tiotropium in COPD. Proceedings of the Annual Meeting of the American Thoracic Society (ATS), San Francisco, USA, 21–25 May 2001.

26. Chodosh S, Flanders JS, Kesten S, et al. Effective delivery of particles with the HandiHaler Dry Powder Inhalation System over a range of chronic obstructive pulmonary disease severity. J Aerosol Med 2001; 14: 309–315.

27 Rand CS, Nides M, Cowles MK et al. Long-term metered-dose inhaler adherence in a clinical trial: The Lung Health Study Research Group. Am J Respir Crit Care Med 1995; 152:580–588.

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Side effects of the drug Tiotropium bromide

From the gastrointestinal tract - dry mouth (usually mild, often disappears with continued treatment), constipation. From the respiratory system: cough, local irritation, possible development of bronchospasm, as well as when taking other inhalation agents. Other: tachycardia, difficulty or retention of urination (in men with prostatic hyperplasia), angioedema, blurred vision, acute glaucoma (associated with anticholinergic effects).

Special instructions for the use of Tiotropium bromide

Careful monitoring of patients with moderate or severe renal impairment receiving tiotropium bromide in combination with other drugs excreted primarily by the kidneys is necessary. Prescribe with caution to patients with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction. It should not be used as a means of emergency treatment to relieve bronchospasm attacks. Do not allow the powder to get into your eyes. Use is contraindicated in the first trimester of pregnancy. During other periods of pregnancy and during breastfeeding - only if the expected benefit outweighs any possible risk to the fetus or infant.