Effect of the beta-blockers propranolol and atenolol and the bronchodilators salbutamol and aminophylline on gastric acid production and motility

The dissertation is devoted to a comparative analysis of the systemic pharmacodynamic effects of widely used cardiotropic (propranolol, atenolol) and broncholytic (salbutamol, euphylline) agents on the functional state of the stomach — acid production and motility — upon their single administration. The work critically summarizes contradictory literature data on the influence of adrenotropic drugs and methylxanthines on parietal cells and the smooth musculature of the gastrointestinal tract, and considers the methodological limitations of various methods of assessing secretion and biopotentials.

Using intragastric teleradio-pH-metry and electrogastroenterography, including with narrow-band filters, acid formation and the electrical activity of the stomach and intestine were studied in patients with different basal acid production and taking into account the individual type of parietal cell reception. Clinical-pharmacological modeling was carried out using omeprazole, pirenzepine, ranitidine, loperamide, pyrroxane and naphazoline, which made it possible to characterize the contribution of different receptor mechanisms. Based on the data obtained, recommendations were formulated for the clinical use of these drugs in patients with combined cardio-respiratory and gastroenterological pathology.

Relevance of the topic:

Objective information on the structural and functional state of the stomach is needed not only to decide on the necessity of pharmacotherapy in dystrophic lesions (erosions, ulcers) and inflammation (gastritis) of the mucosa in primary gastric diseases, but also for the preventive correction of complications in the treatment of other organs and systems, in particular, when non-steroidal anti-inflammatory drugs are used (V.T. Ivashkin, A.A. Sheptulin, 2003).

No less urgent is the problem of changes in gastric motility and acid production under the influence of widely used cardiotropic and broncholytic drugs (V.T. Ivashkin et al., 1990). On the one hand, it is necessary to know the direction and degree of systemic pharmacodynamic effects at the gastric level in order to develop practical recommendations both for the correction of digestion and for the prevention of other principal pathological gastric syndromes (pain, heartburn, heaviness in the epigastrium, belching). On the other hand, changes in motility and acid production may distort the usual pharmacokinetics at the level of absorption and biotransformation of the same cardiotropic agents and broncholytics (L.E. Kholodov, V.P. Yakovlev, 1985; V.G. Kukes, 1999; N.S. Gillies et al., 1986).

In analyzing the specialized literature, the contradictions in the data of different authors attract attention.

The beta-2-adrenostimulator salbutamol inhibits acid production stimulated by food (L.P. Fielding et al., 1978; R.F. McCloy et al., 1979), pentagastrin (M.J. Daly et al., 1978; L.P. Fielding et al., 1978; M. Takeda and T. Takagi, 1980; R.F. McCloy et al., 1979; F. Gottrup, J. Ornsholt, 1978; R.C. Thirlby et al., 1988) or, to a lesser extent, histamine (R.F. McCloy et al., 1979), which to a certain extent may be mediated by activation of somatostatin (K. Bech, K. Uvnas-Moberg, 1986); it also inhibits histamine-stimulated pepsin secretion (R.F. McCloy, V.A. Dawson, J.H. Baron, 1979). However, S.P. Canfield et al., 1981, recorded a stimulating effect of salbutamol on acid production in an isolated rat stomach model.

On the other hand, data exist (R.C. Thirlby et al., 1988) that the beta-2-adrenostimulator terbutaline, although it reduces digestive HCl secretion, increases HCl output against the background of pentagastrin stimulation, while alupent (A.A. Fisher et al., 1990) increases both basal acid production and that against the background of pentagastrin and histamine stimulation in healthy subjects and does not affect histamine-stimulated HCl secretion in dogs.

The non-selective beta-1-2-adrenostimulator isadrine, on the one hand, against the background of pentagastrin stimulation inhibits (C.P. Hovendal et al., 1981; D.F. Magee, 1976; B.H. Hirst, 1988) both the total volume of gastric secretion and the formation of hydrochloric acid and pepsin; but on the other hand, it may itself stimulate acid production (V.I. Gelvakh, 1985; K.V. Okun, Yu.V. Anshelevich, 1980; J. Anschelewitsch, K. Okun, 1976; S.P. Canfield et al., 1981; V. Andreica et al., 1989; P. Canfield, P. Paraskeva, 1992; K. Yokotani et al., 1994).

Regarding theophylline, most authors (G.I. Dorofeev et al., 1977; Yu.M. Kovaliv, 1986; A.M. Semenov and V.P. Kobzev, 1982; A.V. Frolkis, 1991; Ya.S. Tsimmerman and E.S. Golovanova, 1982; J.B. Harris et al., 1969; L.J. Foster et al., 1979; H.I. Jacoby et al., 1979) consider it a stimulator of basal acid production. At the same time, H.I. Jacoby et al., 1979, found that theophylline does not affect histamine-stimulated acid production and even suppresses HCl output in response to stimulation by gastrin and insulin. M. Lazzaroni et al., 1990, with intravenous administration of aminophylline found no dynamics in gastric secretion at all.

All authors (M. Takeda, T. Takagi, 1980; M.J. Daly et al., 1978; F. Gottrup, J. Ornsholt, 1978; V. Andreica et al., 1989; D.F. Magee, 1976; B.H. Hirst, 1988; P. Canfield, P. Paraskeva, 1992; R.F. McCloy et al., 1979; F. Gottrup et al., 1979, 1980; S.P. Canfield et al., 1981) recognize that propranolol prevents all pharmacodynamic effects at the level of gastric secretion caused by adrenaline, noradrenaline, isadrine, salbutamol, alupent, terbutaline, salme famol and that practolol (a beta-1-adrenoblocker) and alprenolol (beta-1-2), which possess intrinsic sympathomimetic activity, do not have the indicated property. In other words, as a rule, propranolol stimulates acid production, which is consistent with the data of A.B. Kazaryan et al., 1989; T.I. Selivanova et al., 1985; V.T. Ivashkin et al., 1990, on basal acid production and on propranolol stimulation of pentagastrin-stimulated HCl secretion (A.A. Fisher et al., 1990; B.H. Hirst, 1988; R.F. McCloy et al., 1979; S. Okabe et al., 1977).

In the pharmacological effect of propranolol, therefore, vagotropic traits are traced (F. Gottrup et al., 1979 and 1980).

However, there are works (L.P. Vorobyev and I.V. Maev, 1988; A.V. Frolkis, 1991; Yu.V. Anshelevich and K.V. Okun, 1976; K.V. Okun and Yu.V. Anshelevich, 1980; S. Konturek, J. Olesky, 1969; O. Kronborg, 1975; E. Zukowska-Szizechowska, 1990; A. Lanas et al., 1988) showing an inhibitory effect of propranolol on basal and variously stimulated acid production.

V. Andreica et al., 1989, suggest that the gastric secretory reaction is largely determined by unaccounted individual characteristics of the subject: propranolol leads to achlorhydria in 30.7% of cases, reduces the basal level in 42.3%, increases it in 1.9%, has no effect in 25%, and against the background of histamine stimulation reduces HCl secretion in 57% and increases it in 43%.

The fact of propranolol inhibiting insulin-stimulated HCl secretion (T. Banciu, I.O. Rada, 1985) and insulin secretion itself (T. Ikeda et al., 1993) is also known.

The suppressive effect of propranolol on acid production in some cases may be due to inhibition of carbonic anhydrase (I. Puscas et al., 1986), which supplies Cl⁻ ions at the final stage of HCl synthesis in the gastric lumen.

Phentolamine (alpha-1 and 2-adrenoblocker) does not directly affect acid production (B.H. Hirst, 1988), but through activation of secretin upon acidification of the duodenal zone (A. Lanas et al., 1988) it inhibits gastric secretion.

The demonstrative inconsistency of scientific data on the influence of adrenotropic mediators and xenobiotics on gastric secretion is explained by many factors, among which are the initial functional state of the parietal cells (A.A. Fisher and V.I. Gelvakh, 1985; V.I. Gelvakh, 1985; E.Yu. Dinar, 1968) and including the predominant individual type of parietal cell reception according to the annual biorhythm (I.L. Blinkov et al., 1987; E.V. Selina, 1988), methodological features of gastric juice examination (A.M. Ugolev et al., 1969; A.Ya. Antsans, 1983; K.V. Bezzubik et al., 1987; V.A. Gorshkov, 1988; V.T. Ivashkin, 1970; Yu.Ya. Leya, 1987; V.G. Mysh, 1985; V.P. Curwain et al., 1972), concomitant pathology, especially the degree of gastric mucosal atrophy, the variant of juice secretion stimulation, and experimental conditions (including animal species, use of anesthesia, acute or chronic experiment, gastric fistula, surviving organs or tissues and cells).

Adrenaline enhances Ca entry into the cell. Beta-adrenoblockers inhibit Ca entry into the cell and exert a direct vagotropic action, in particular, enhancing the tone of propulsive muscles of the gastrointestinal tract.

It has been shown (A.V. Frolkis, 1981) in an experiment the inhibitory effect of euphylline on small intestinal motility. Isadrine inhibits the tone and motility of the stomach (V.T. Ivashkin et al., 1990), small intestine (M.J. Neel, 1999) and large intestine (A.V. Frolkis, 1981).

Fluctuations of the membrane potential, independently of nervous influences, food intake and other physiological factors, cause rhythmic contractions of smooth muscles that maintain hollow organs in a state of a definite basal tone (I.A. Aleshin et al., 1983; A.V. Kalinin and L.I. Butorova, 2001; A.D. Nozdrachev et al., 2001; J.M. Polak et al., 1989).

The contradiction in the data of different researchers (S.N. Golikov and Yu.I. Fishzon-Ryss, 1978; V.Kh. Vasilenko and E.N. Kochina, 1983; J.M. Polak et al., 1989; V.T. Ivashkin, 1981; A.V. Frolkis, 1981, 1991, 2000; I.A. Aleshin et al., 1983) on this issue is due both to the multi-level and very complex regulation of the tone and motility of the gastrointestinal tract, and to the differences in the instrumental control methods used, each of which has its own informational limits and its own artifacts.

S.N. Golikov and Yu.I. Fishzon-Ryss, 1978, on the basis of a comparative analysis of instrumental methods of gastrointestinal motility control, came to the conclusion that balloon-kimography provides information on the tone of the long muscles of the stomach, while electrogastrography provides information on the antropyloric region.

According to A.V. Frolkis, 1981, 1991, 2000, I.L. Myasnikov, 1997; V.Kh. Vasilenko and E.N. Kochina, 1983; S.N. Golikov and Yu.I. Fishzon-Ryss, 1978; J.M. Polak et al., 1989; A.A. Mihas, 1982; H. Abrahamsson et al., 1983; M. Hirohashi et al., 1990; W.H. Percy et al., 2002; M. Takeda, T. Takagi, 1980, beta-adrenoblockers enhance the motility of the gastrointestinal tract, which is recorded not only by instrumental methods but also by ordinary clinical observation (cessation of constipation). However, there is an opinion (V.T. Ivashkin, 1981) that agents that change the functional state of beta-adrenoceptors do not affect gastric motility at all. The contradiction in data on the influence of the state of beta-adrenoceptors on the tone and motility of the gastrointestinal tract is explained by various reasons, in particular, by the initial structural and functional state of the organs (E. Lyrenas et al., 1985), when the same effect produces an opposite response. The response may depend on the dose of the drug not only by the influence on different parts (J.M. Polak et al., 1989; S.N. Golikov and Yu.I. Fishzon-Ryss, 1978) of the gastrointestinal tract (GIT), which have their own local pacemakers (A.V. Frolkis, 1981, 1991; K.V. Sudakov, 1999), but also in the same zone due to the involvement of different receptor fields and different types of autonomic fibers (M.A. Medvedev et al., 1984) or the predominance of a microelement ligand composition. Different methods of motility control can be used (I.A. Aleshin et al., 1983; S.N. Golikov, Yu.I. Fishzon-Ryss, 1978; V.Kh. Vasilenko, E.N. Kochina, 1983), designed for different levels of gastrointestinal organization and having specific artifacts in interpreting the results. Not all researchers take into account the temporal factor in terms of receptor hyperreactivity after cessation of exposure to the studied drug (S.N. Golikov, Yu.I. Fishzon-Ryss, 1978; I.A. Aleshin et al., 1983). With rare exceptions (I.A. Aleshin et al., 1983; J.M. Polak et al., 1989; Zh.P. Smirnova and V.S. Omelyanyuk, 1989), the participation of the glandular apparatus of the mucosa in the generation of biopotentials of electrogastrograms, whose state changes under the influence of the same mediators as smooth muscles, is not taken into account at all. There is practically no data on the comparative effect on tone and motility of non-selective and selective beta-adrenoblockers.

The presence of powerful electrolyte fluxes of H⁺ and K⁺ (D.A. Kharkevich, 1999) and — indirectly — Cl⁻ (Zh.P. Smirnova, V.S. Omelyanyuk, 1989) in the glandular cells of the mucosa, especially of the stomach, makes it necessary to take into account the role of the mucosa in the biopotential activity of the GIT.

The role of the glandular apparatus in the generation of spontaneous biopotential activity (SBA) of the GIT was most fully elucidated by I.A. Aleshin et al., 1983, and J.M. Polak et al., 1989, who confirmed this hypothesis using microelectrode techniques: rhythmic slow waves of gastric SBA with large amplitude arise in the mucosa, and small and frequent waves arise secondarily in the muscle layer (like a cardiomyogram — after being triggered by the endocardial conduction system). Stimulation of acid production by pentagastrin or histamine sharply changes inter-digestive muscle contractions immediately and then through the involvement of intestinal regulatory polypeptides (neurotensin). In particular, against the background of digestive relaxation of the stomach, a reciprocal enhancement of sigmoid motility is observed (gastrocolic reflex).

A decrease in HCl concentration in the stomach or an otherwise achieved increase in the alkalinity of the duodenal contents leads to enhancement of small intestinal motility (V.T. Ivashkin et al., 1990; K.V. Sudakov, 1999; J.M. Polak et al., 1989).

Thus, it seems relevant to conduct a comparative analysis of the influence of salbutamol, euphylline, atenolol and propranolol on the functional state of the stomach using optimal methods for monitoring acid production and motility.

Aim of the study:

To study the systemic pharmacodynamic effects of propranolol, atenolol, salbutamol, and euphylline on gastric acid production and motility upon single administration.

Tasks of the study:

1. To study the effect of a single administration of 10 mg propranolol, 50 mg atenolol, 4 mg salbutamol and 150 mg euphylline on gastric acid formation in patients with high and medium intensity of basal acid production (pHbas. < 3), taking into account the individual type of parietal cell reception of the stomach (ITROKZH).

2. In patients with low intensity of acid production (3 < pHbas. < 6) in the stomach, to study the effect of 150 mg euphylline on acid formation and to evaluate its severity at different levels of basal pH.

3. To investigate the diagnostic capabilities of the euphylline test (with 150 mg of the drug) used during intragastric pH-metry in patients with a low level of basal acid production.

4. To study the effect of propranolol, atenolol, salbutamol and euphylline on gastric motility using electrogastroenterography by means of spectral analysis of biopotential recordings in comparison with the method using narrow-band filters.

5. To identify patterns of the systemic pharmacodynamic influence of propranolol, atenolol, salbutamol and euphylline on motility, taking into account the data of clinical-pharmacological modeling of the functional state of the gastrointestinal tract using omeprazole, pirenzepine, ranitidine, loperamide, pyrroxane and naphazoline.

6. To develop recommendations on the features of the clinical use of propranolol, atenolol, salbutamol and euphylline in patients with combined diseases of the heart or bronchi with gastric pathology.

Scientific novelty:

For the first time, to identify the systemic pharmacodynamic effects of the cardiotropic agents propranolol and atenolol and the broncholytics salbutamol and euphylline at the level of the functional state of the stomach, the methods of intragastric teleradio-pH-metry and biopotential recording with narrow-band filters have been applied.

It has been shown for the first time that the effect of propranolol, atenolol, salbutamol and euphylline on the functional state of the stomach does not depend on the individual type of parietal cell reception of the stomach, which is responsible according to the annual biorhythm for the initiation and blockade of acid production at the time of the study.

For the first time, by means of a comparative analysis of the results of clinical-pharmacological modeling, it has been shown that electrogastroenterography with narrow-band filters allows observing the dynamics of the state of the circular muscles of the gastrointestinal tract.

For the first time, it has been established that the onset of the systemic pharmacodynamic effect on the functional state of the stomach of propranolol, atenolol, salbutamol and euphylline does not depend on pharmacokinetics, but is mediated by a direct effect on the receptor apparatus of the stomach within the first half-hour after oral administration.

The following main statements are submitted for defense:

1. Both muscular structures and the mucosa participate in the generation of biopotentials of the gastrointestinal tract.

2. Biopotential recording with narrow-band filters allows observing the functional state of the circular muscles of the gastrointestinal tract.

3. There are no definite correlative connections between the physiological direction of the influence of propranolol, atenolol, salbutamol and euphylline on the parameters of acid production and motility.

4. Beta-2-adrenoceptor agonists inhibit gastric acid production both directly and indirectly — upon blockade of beta-1-adrenoceptors, while blockade of beta-2-adrenoceptors leads to stimulation of free acid formation.

Publications:

Based on the materials of the dissertation, 5 scientific papers have been published.

Approbation of the work:

The results of the work were discussed at a joint conference of the Department of Clinical Laboratory and Propaedeutics of Internal Diseases of I.M. Sechenov Moscow Medical Academy, the Laboratory of Clinical Pharmacology of I.M. Sechenov Moscow Medical Academy, and the Problem Laboratory for the Development, Study, Implementation, Production and Marketing of Medicines of the RAMS, on December 26.

Volume and structure:

The dissertation is set out on 139 pages of typewritten text and consists of an introduction, a literature review, materials and methods, two sections of the chapter of the author's own studies, a discussion, conclusions and practical recommendations, and an appendix. The dissertation is illustrated with 23 figures, 4 schemes and 43 tables. The bibliography includes 85 domestic and 49 foreign sources.