Antisecretory agents- This is a group of medicines that reduce the production of hydrochloric acid by acting on parietal cells and blocking the main mechanisms of secretion. With an increase in the concentration of hydrochloric acid, the development of various gastric diseases is observed: ulcers, gastritis, heartburn, ulcerative colitis. Antisecretory drugs can accelerate the process of scarring of damaged membranes. The use of this group of drugs as a remedy for heartburn is possible only if the disease causing such a symptom is ineffective and severe.
H2-histamine blockers
used in acid-dependent diseases of the digestive tract. The drug blocks histamine receptors in the gastric mucosa, reducing the production and entry of acid into the gastric lumen. They are more outdated drugs than proton pump inhibitors in terms of the duration of acid suppression action, as well as the number of possible adverse reactions.
proton pump inhibitors
They are one of the most effective groups of drugs that are prescribed to patients with gastric ulcer, including provoked. Initially, this is a prodrug, but after entering the digestive tract and attaching hydrogen protons, a transformation into a dosage form is observed. Active substances bind to parietal cells (their enzymes) and inhibit acid synthesis.
Proton poma inhibitors include drugs based on the following active ingredients:
For the treatment of gastrointestinal diseases caused by the pathogen Helicobacter pylori, the active substances of proton pump inhibitors are in combination with antibiotics: clarithromycin, amoxicillin, levofloxacin.
M-anticholinergics
- an outdated group of drugs that was used in the treatment of stomach ulcers. At the moment, preference is given to more modern and effective drugs. M-anticholinergics block M-cholinergic receptors, reducing basal and stimulated secretion. M-anticholinergics are:
- non-selective: preparations based on metocinium iodide, chlorosyl.
- selective: Gastrocepin.
Under the influence of drugs of this group, there is a decrease in tone, amplitude, frequency of peristaltic contractions, relaxation of sphincters.
Features of the use of antisecretory drugs in various pathologies
H2-histamine blockers used for the following indications:
proton pump inhibitors shown to patients with:
M-anticholinergics based on pirenzepine is used in the treatment of patients with mild to moderate gastric ulcer. In some cases, doctors prescribe a combination treatment with the addition of drugs from the group of H2-histamine blockers.
Contraindications
| Drug group | Absolute | relative |
| H2-histamine blockers |
|
|
| proton pump inhibitors |
|
|
| M-anticholinergics |
|
|
Side effects
H2-histamine blockers
Prolonged use of the drug |
|
Impact on the digestive tract |
|
Effects on sex hormones | Most often, against the background of the use of cimetidine, development is observed:
|
| Effects of histamine receptors on other organs |
|
proton pump inhibitors
Gastrointestinal tract |
|
| Musculoskeletal system |
|
| excretory system |
|
central nervous system |
|
| Blood system |
|
Other reactions | Allergic reactions:
|
M-anticholinergics
M-anticholinergics can cause dry mouth, decreased sweating, dilated pupils. With the maximum severity of adverse reactions, swallowing and urination becomes difficult, body temperature rises.
a) H + /K + -ATPase inhibitors or proton pump inhibitors(IPN) occupy a central place among antiulcer drugs. Firstly, this is due to the fact that they are significantly superior to other drugs in terms of antisecretory activity, and, consequently, in terms of clinical efficacy. Secondly, PPIs create a favorable environment for the anti-helicobacter effect of AB, so they are included in all H. pylori eradication schemes. Of the drugs in this group in pediatric practice is currently used omeprazole, in the internist clinic are widely used pantoprazole, lansoprazole, rabeprazole.
Pharmacodynamics. The antisecretory effect of these drugs is realized not by blocking the receptors involved in the regulation of gastric secretion, but by directly affecting the synthesis of HCl. The functioning of the acid pump is the final stage of biochemical transformations inside the parietal cell, which result in the production of hydrochloric acid (Figure 3).
Figure 3 - Mechanisms of action of antisecretory agents
PPIs initially do not have biological activity. But, being chemically weak bases, they accumulate in the secretory tubules of parietal cells, where, under the influence of hydrochloric acid, they are converted into sulfonamide derivatives, which form covalent disulfide bonds with the H + /K + -ATPase cysteine, inhibiting this enzyme. To restore secretion, the parietal cell is forced to synthesize a new enzyme protein, which takes about 18 hours. The high therapeutic efficacy of PPIs is due to their pronounced antisecretory activity, which is 2-10 times higher than that of H2-blockers. When taking an average therapeutic dose once a day (regardless of the time of day), gastric acid secretion during the day is suppressed by 80-98%, while when taking H2-blockers - by 55-70%. As such, PPIs are currently the only drugs capable of maintaining intragastric pH above 3.0 for more than 18 hours, and thus meet Burget's requirements for ideal anti-ulcer agents. PPIs do not have a direct effect on the production of pepsin and gastric mucus, but, in accordance with the “feedback” law, they increase (1.6-4 times) the level of gastrin in the serum, which quickly normalizes after stopping treatment.
Pharmacokinetics. When taken orally, PPIs of the proton pump, getting into the acidic environment of gastric juice, can prematurely turn into sulphenamides, which are poorly absorbed in the intestine. Therefore, they are used in acid-resistant capsules. The bioavailability of omeprazole in this dosage form is about 65%, pantoprazole - 77%, for lansoprazole it is variable. Drugs are rapidly metabolized in the liver, excreted through the kidneys (omeprazole, pantoprazole) and the gastrointestinal tract (lansoprazole). The safety profile of PPIs for short (up to 3 months) courses of therapy is very high. Most often, headache (2-3%), fatigue (2%), dizziness (1%), diarrhea (2%), constipation (1% of patients) are noted. In rare cases, allergic reactions in the form of a skin rash or bronchospasm. With long-term (especially for several years) continuous intake of PPIs in high doses (40 mg of omeprazole, 80 mg of pantoprazole, 60 mg of lansoprazole), hypergastrinemia occurs, atrophic gastritis progresses, and sometimes nodular hyperplasia of enterochromaffin cells of the gastric mucosa. But the need for long-term intake of such doses is usually only in patients with Zollinger-Ellison syndrome and in severe erosive-ulcerative esophagitis, which is extremely rare in pediatric practice. Omeprazole and lansoprazole moderately inhibit cytochrome P-450 in the liver and, as a result, slow down the elimination of certain drugs (diazepam, warfarin). At the same time, the metabolism of caffeine, theophylline, propranolol, quinidine is not disturbed.
Release form and dosage.
Omeprazole(omez, losek, zerocid, ultop) is available in capsules of 0.01; 0.02; 0.04, in vials of 42.6 mg of omeprazole sodium (equivalent to 40 mg of omeprazole) for intravenous administration. It is used from 6 years old at 10-20 mg 1 time per day before breakfast. With Zollinger-Ellison syndrome, the maximum allowable daily dose may be 120 mg, when taking more than 80 mg / day, the dose is divided into 2 times. Currently, new forms of omeprazole have appeared on the pharmaceutical market of the Republic of Belarus: omez insta(20 mg omeprazole + 1680 mg sodium bicarbonate), omez dsr(20 mg omeprazole + 30 mg delayed-release domperidone).
Esomeprazole(nexium) – the only left-handed isomer of omeprazole (all the rest are racemates), is available in tablets of 0.02, approved for use from 12 years old, 1 tablet 1 time per day before breakfast. Tablets must be swallowed whole, not chewed or crushed, can be dissolved in still water.
b) blockers of H 2 -histamine receptors began to be used in clinical practice since the mid-70s, after J. Black synthesized the first H2-histamine receptor blockers (burimamide and methiamide) in 1972, but in clinical trials they turned out to be ineffective and caused a large number of side effects. Several generations of these drugs are known, after cimetidine(1974) were successively synthesized ranitidine, famotidine, and a little later - nizatidine And roxatidine. According to the chemical structure, the drugs of this group differ somewhat from each other: cimetidine contains an imidazole ring in its structure, and all other drugs contain a furan one, which several times increases their effectiveness and reduces the number of undesirable side effects.
Pharmacodynamics. The main effect of H 2 -blockers is antisecretory: due to the competitive blocking of H 2 -histamine receptors in the gastric mucosa, they suppress the production of hydrochloric acid. New generation drugs are superior to cimetidine in the degree of suppression of nocturnal and total daily secretion of hydrochloric acid, as well as in the duration of the antisecretory effect (table 15).
Table 15 - Comparative pharmacodynamics of H 2 -histamine blockers
In addition to inhibiting the secretion of hydrochloric acid H 2 -blockers have a number of other effects. They suppress basal and stimulated production of pepsin, increase the production of gastric mucus and bicarbonates, enhance the synthesis of prostaglandins in the stomach wall, and improve microcirculation in the mucosa. In recent years, it has been shown that H2-blockers inhibit mast cell degranulation, reduce the histamine content in the periulcerous zone, and increase the number of DNA-synthesizing epithelial cells, thereby stimulating reparative processes.
Pharmacokinetics. When taken orally, H 2 -blockers are well absorbed in the proximal small intestine, reaching peak blood concentrations in 30-60 minutes. The bioavailability of cimetidine is 60-80%, ranitidine - 50-60%, famotidine - 30-50%, nizatidine - 70%, roxatidine - 90-100%. Excretion of drugs is carried out through the kidneys, and 50-90% of the dose taken is unchanged. The half-life of cimetidine, ranitidine and nizatidine is 12 hours, famotidine - 25-35 hours, roxatidine - 16 hours.
Cimetidine is not currently used due to the large number of adverse reactions. The next generations - ranitidine, famotidine, nizatidine and roxatidine - are much better tolerated, they do not have antiandrogenic and hepatotoxic effects, do not penetrate the blood-brain barrier and do not cause neuropsychiatric disorders. When they are used, only dyspeptic disorders (constipation, diarrhea, flatulence) and allergic reactions (mainly in the form of urticaria), which are relatively rare (1-2%), can be noted. With prolonged use of H 2 blockers (more than 8 weeks), especially at high doses, one should keep in mind the potential for the development of hypergastrinemia with subsequent hyperplasia of enterochromaffin cells in the gastric mucosa.
Release form and dosage.
Ranitidine(umbrella, ranisan, gistak, gi-car) - II generation. Available in tablets of 0.15 and 0.3, ampoules of 50 mg / 2 ml. It is prescribed in pediatric practice at the rate of 4-8 mg / kg / day, but not more than 300 mg, divided into 2 doses.
famotidine(famocide, kvamatel, ulfamid, famo, famosan, panalba) - III generation. Available in tablets of 0.02 and 0.04, ampoules of 0.02. It is prescribed once at the rate of 0.5-1.0 mg / kg / day, but not more than 40 mg per day. Preparations IV (nizatidine) and V (roksatidine) generations in pediatric practice are not used.
N.B! When using H 2 -histamine blockers, you should remember:
With prolonged use of them, a transient increase in the activity of liver transaminases can be observed,
With the rapid intravenous administration of ranitidine, the development of bradycardia, hypotension, allorhythmia and even asystole is possible,
After the main course of treatment, a transition to a maintenance dose is necessary in order to avoid the "rebound" syndrome.
Their main clinical purpose is to suppress relatively or absolutely excessive acid and enzyme formation. At the same time, a number of clinical manifestations caused by acid-peptic effects are eliminated.
Such properties are endowed with a number of substances belonging to various pharmacological groups. Of these, first of all, we will focus on anticholinergics.
Cholinolytic (anticholinergic) drugs. These drugs can be divided into non-selective and selective. The first of them have been known for a long time. These include atropine, metacin, chlorozil, platinum. The last of them is endowed with only weak anti-secretory properties. Metacin shows them almost exclusively when administered parenterally, which significantly limits the possibility of its effective clinical use [Golikov SI, Fishzon-Ryss Yu. I., 1978]. Chlorosil, although endowed with a pronounced and prolonged antisecretory effect, has not yet entered into everyday practice. Thus, atropine remains the main representative of the agents under consideration.
The advantages of atropine include rapid and complete absorption from the digestive tract, a pronounced antispasmodic and antisecretory effect. However, the latter is characterized by a relatively short duration - about 1.5 hours, after which there is an activation of secretion, which sometimes begins to exceed the initial level. It is important that with the help of atropine it is not possible to achieve a stable suppression of gastric juice secretion, which is also prevented by its excessively wide spectrum of action and toxicity, which serve as a source of adverse reactions. The foregoing explains why atropine and other belladonna derivatives are currently used in gastroenterology mainly as antispasmodic rather than antisecretory agents. This makes it superfluous a detailed description of the last side of the activity of atropine, information about which can be found in our previous publication on anticholinergic and adrenoblocking agents [Golikov SN, Fishzon-Ryss Yu. I., 1978].
Selective blockers of Mi-cholinergic receptors. The discovery of the heterogeneity of M-cholinergic receptors, in particular the establishment of two
their subtypes - Mi- and Ms-cholinergic receptors - forced to reconsider the traditional ideas about anticholinergics as a homogeneous pharmacological group. It is important to emphasize that the localization of m]- and Ma-cholinergic receptors in the digestive system does not coincide. This opened up the possibility of synthesizing a drug that selectively affects Mi-cholinergic receptors - pirenzepine (gastrocepin). Mi-cholinergic receptors are present in the intramural ganglia in the submucosa, while Mz-receptors blocked by atropine are present in the membranes of parietal cells
Pirenzepine is a derivative of tricyclic pyrido-benzodiazepine, which is similar in its chemical structure to anti-depressants, but unlike the latter, it does not penetrate the central nervous system. Although pirenzepine is somewhat inferior to atropine in the strength of the antisecretory effect, it is much superior to the latter in its duration. It has been established that the half-life of pirenzepine is about 10 hours, and already after 4 days of using its therapeutic doses, an almost constant concentration of this drug in the blood is established. According to a number of authors, pirenzepine reduces the level of maximum and basal acid production and the debit of pepsinogenia by approximately /4-/z. However, pirenzepine does not have a significant effect on the motor activity of the stomach and the tone of the lower esophageal sphincter, which is reduced by atropine.
The mechanism of antisecretory activity of pirenzepine is not yet fully understood. There is reason to believe that, in addition to the blockade of Mi-cholinergic receptors of autonomic ganglia, it has a blocking effect on inhibitory M-cholinergic receptors of somatostatin cells of the gastric fundus. At the same time, pirenzepine does not have a significant effect on cardiac activity, salivary glands and eyes, and therefore is well tolerated. Being a tricyclic compound, pirenzepine nevertheless does not penetrate the blood-brain barrier, and therefore lacks central activity. All of the above justifies the isolation of pirenzepine as a selective anticholinergic. Among other aspects of the action of pirenzepine, we note the possibility of its cytoprotection
effect not mediated by catecholamines and endogenous prostaglandins. Recently, it has been shown that the antiulcerogenic effect of pirenzepine is more due to its antisecretory than cytoprotective properties. Pirenzepine (gastro-cepin) with exacerbation of peptic ulcer is prescribed orally at 100-150 mg (table 4-6) per day 30 minutes before meals or intramuscularly at 10 mg of dry matter 2 times a day. The course of treatment - 4 - b weeks.
Hg-histamine receptor blockers. Enough time has passed since the appearance of the first prolstgzhitelsi of this group * and - to the egg "!
Blockade of H3-histamine receptors leads to a decrease in histamine stimulation of the gastric glands (Fig. 1, B, 2). Three kinds of assumptions have been made about the more subtle mechanisms of realization of the secretory effect of histamine. The first is that histamine is a common mediator released by acetylcholine and gastrin. The second is the presence of a close interaction of three types of receptors - gastrin, acetylcholine and histamine, the blockade of any of which causes a decrease in the sensitivity of the other two. The third assumption is based on the idea of the decisive role of histamine in maintaining the tonic background in the parietal cells, which sensitizes them to the action of other stimuli.
Blockers of H3-histamine receptors suppress basal gastric secretion stimulated by gastrin, pentagastrin, histamine, caffeine, food and mechanical irritation, and the differences in the effect of comparable doses of individual drugs are small. Thus, it was found that cimetidine reduced the acidity of the maximum histamine secretion by 84%. Famotidine at a dose of 5 mg reduced the release of acid in patients with duodenal ulcer during pentagastrin stimulation of secretion by 60%, and when the dose was increased to 10 and 20 mg, by 70 and 90%, respectively. After weekly use of 1600 mg/day of cimetidine or 300 mg/day of ranitidine in patients with duodenal ulcers, pepsin secretion decreased by 63-65%, and hydrochloric acid - by 56% of the initial level.
With exacerbation of peptic ulcer, cimetidine is prescribed 0.2 g orally after each meal and 0.4 g at night or 0.4 g after breakfast and at bedtime. Ranitidine in such patients is recommended to use 150 mg orally 2 times a day or 300 mg at night. Famotidine (MK-208) has a prolonged action and is prescribed 20 mg orally 2 times a day or 40 mg at night. The course of treatment is usually 4-8 weeks.
The first H3 receptor antagonists were obtained based on the principle of mimicking the histamine molecule. This can be seen from a comparison of the chemical structure of histamine and H3-histamine receptor blockers:
Subsequently, the synthesis of 1-L-blockers was expanded by creating more complex chemical structures, in which, however, the “anchor” groups for the Hg-histamine receptor groups (imidazole, thiazole, guanidine-thiazole) were retained. This could enhance the effect by giving the molecule conformations close to the molecular environment of the active center of the receptor. These include loxtidine obtained recently abroad and compounds of the WY and MK series, which are superior in their activity to even the most effective
parata MK-208 - a derivative of guandinethiazole, equal to 5 mg, equivalent to 300 mg of cimetidine. With regard to the duration of action, some progress has been made here. Filed by G. Laferia (1986), mifentidine and zaltidin are significantly superior in this respect to other Ngistamine receptor blockers. However, the “pursuit” of efficacy and duration of action is not the only reason for the intensive search for new compounds in this pharmacological group. Equally important, and sometimes predominant, is the desire to obtain a drug devoid of side effects characteristic of a number of blockers, especially with their long-term use. To the greatest extent, side effects are expressed in cimetidine. These include impotence, gynecomastia, mental disorders up to dementia, lymphocytopenia and thrombocytopenia, diarrhea, various rashes, headache, decreased functional activity of the liver, increased activity of transaminases. These adverse events, however, are relatively rare and usually do not reach significant severity. They almost do not dry ranitidine and famotidine.
In the clinical use of H2-histamine blockers, one has to take into account their effect on the metabolism of other drugs, the oxidation of which by microsomal enzymes of liver cells can be disturbed.
The assessment of the effect of H3-histamine receptor blockers on the resistance of the gastroduodenal mucosa remains controversial. If some point to the cytoprotective effect of these agents, others deny such an effect. In addition, there are suggestions about the ability of the considered agents to improve microcirculation in the tissues of the stomach, which can prevent the formation of shock ulcers.
The combination of these positive therapeutic properties and mainly pronounced antisecretory action explains the high clinical efficacy of H3-histamine blockers in peptic ulcer disease. According to summary data, for a 4-6-week period of their use, scarring of ulcers is achieved in approximately 80%, and in 8 weeks - in 90% of patients, and with duodenal localization of the ulcer somewhat more often than with gastric.
Suppression of the production of hydrochloric acid is also possible by changing the permeability of the cell membrane, blocking the synthesis of the transport protein or the protein of the cellular mcvi-brane, direct influence on the exchange or transport processes inside the parietal cells, etc.
Hydrogen ion transport blockers. In the 60s, it was found that ATP generated in the mitochondria of the parietal cells of the gastric mucosa serves!!! pstochgko! -iii; gies for the transport of hydrogen ions. The discovery of a special transport Na4", K^-activated ATPase and its importance in the active transport of ions across membranes prompted researchers to study the role of this system in the transport of ions during the formation of hydrochloric acid in the gastric mucosa. Data were obtained on the suppression of activity by thiocyanate ions ATPase, but the very fact of inhibition of gastric secretion by thiocyanate by interfering with the secretion process at the biochemical level for a long time remained in the shadow of the successes achieved in the study and use of histamine H-receptor blockers.It was remembered when it was shown that some substituted benzimidazoles have an effect on the secretory glands similar to thiocyanate.First, timoprazole was obtained, which showed universal antisecretory activity in various experimental models of peptic ulcer, and then omeprazole, which turned out to be much more active and less toxic than timoprazole.
It can be considered firmly established that omeprazole affects the final link in the production and release of acid at the biochemical stage of this process. It blocks the enzyme H^, K^-ATPase, which ensures the transport of H^ from cells and K^ into cells (proton pump). The evidence is:
Substituted benzimidazoles inhibit the secretion of HC1 in dogs and rats with approximately the same effect, regardless of the nature of
stimulations (basal secretion, histamine, pentagastrpi, olinergic agents):
- - in experiments in vitro on isolated glands and parietal cells of the mucous membrane of the stomach of a rabbit, omsprazol inhibited both basal and stimulated gpsamshyum iln di-butyryl cAMP secretion. In the same experiments, cimetidine inhibited only histamine-stimulated secretion,
- - by autoradiographic method at the ultrastructural level -
pain, mainly on the secretory surface of the cell in the area of its interaction with H "1". K^-ATPase;
- - imeprazole caused a dose-dependent inhibition of the activity of H^, K^-ATPase in isolated membrane vesicles;
- - in experiments on the preparation of microsomal membranes of the gastric fundus mucosa, omeprazole dose-dependently inhibited the activity of this enzyme with an inhibition constant of 2.5 μM:
- - omeirazole inhibited purified H^, K^-ATPase, and this effect increased with decreasing pH of the incubated solution:
- - labeled omerrazole was included in the ATPase preparation depending on time and pH with an inclusion level of 4-5 nmol/mg of protein:
- - omeprazole inhibited the intracellular stimulating effect of 8-bromo cAMP 10 M on the incorporation of labeled aminopyrine into the gastric glands.
According to D. Keeling et al. (1986), the activity of omeprazole is most pronounced under conditions that stimulate the work of the proton pump in functioning vesicles. Data on the possibility of eliminating the action of omeprazole with drugs containing sulfhydryl groups (mercaptoethanol and other exogenous mercaptans) suggest that the molecular mechanism of action of omeprazole is based on the formation of a complex with H4, K "^ - ATPase through disulfide bonds. To date, a sufficient amount of evidence has been obtained that omeprazole is the most powerful universal long-acting inhibitor of gastric secretion. Some reports provide data on the possibility of using omeprazole to achieve 100% suppression of gastric secretion. According to C. Cederberg et al. (1985), the duration of action of a single dose of omeprazole in animal experiments is 2-3 days. In humans, the effect of a single dose persists for a day. In healthy subjects, omeprazole, at a dose of 80 mg intravenously for 10 days, can cause achlorhydria without changing the production of intrinsic factor.
Patients with duodenal ulcers are prescribed omeprazole for 4 weeks once at a dose of 20-40-60 mg, 15 minutes before breakfast. There is evidence that in high doses omeprazole stimulates the formation of carcinoid tumors in animals. At the same time, works appeared on the cytoprotective effect of some analogues of omeprazole (hexaprozole), but they have not yet been clinically tested.
The increased attention we paid to omeprazole may seem redundant, since it has not yet entered wide clinical practice. LLcib, however, has every reason to believe that this is not far off. In addition, an active search for other drugs of this group is currently being carried out, which may open up additional, yet difficult to assess, prospects for their successful clinical use.
Professor Vorobyova NadezhdaAlexandrovna.
Lecturer: Candidate of Medical Sciences, Associate Professor of the Department Belyakova Irina Vyacheslavovna.
Presentation on the topic:
Antisecretory drugs (proton inhibitors)
pumps, blockers of histamine H2 receptors)»
Performed:
6th year student
Faculty of Pediatrics
2 groups
Alekseeva Ksenia Andreevna.
Arkhangelsk
2017
Antisecretory drugs
is a group of drugs that reducegastric secretion due to inhibition of secretion
hydrochloric acid by parietal cells.
These include:
Proton pump inhibitors (H, K + ATPase blockers);
Histamine H2 receptor blockers;
M-anticholinergics
- Selective (M1-anticholinergics),
- Non-selective.
The mechanism of regulation of hydrochloric acid production and its inhibition.
proton pump inhibitors.
Representatives: omeprazole (Losek),pantoprazole (Controloc), rabeprazole
(Pariet), lansoprazole (Lanzap),
esomeprazole (Nexium).
Combined: Pylobact (omeprazole +
clarithromycin + tinidazole), Zegeride
(omeprazole + sodium bicarbonate).
Pharmacodynamics.
After ingestion, being weakbases, they accumulate in an acidic environment
secretory tubules of the parietal cell
close proximity to K + / H "-ATP-ase
(proton pump), which ensures the exchange
protons into potassium ions located in
extracellular space.
There PPIs that are benzimidazole
derivatives, at pH< 3,0 протонируются и
converted to tetracyclic sulfenamide,
from a prodrug to an active form. At
higher pH values (about 3.5-7.4) this
the process slows down.
Pharmacodynamics.
Sulfenamide is a charged molecule and therefore does notpenetrates through cell membranes, remaining inside
secretory tubules of the parietal cell. Here he is
irreversible (with the exception of lansoprazole) covalently
binds to the sulfhydryl groups of K + / H "-ATPase, which
completely blocks its work.
After oral administration of drugs, their antisecretory effect
develops within about 1 hour and reaches a maximum
after 2 hours. The duration of the antisecretory effect is determined
update rate of proton pumps - about half of
they are updated in 30-48 hours. When you first take PPI
antisecretory effect is not maximal, since not
all K + / H "-ATPase molecules are in an active state.
PPIs are characterized by a relatively slow onset
action (not earlier than 30-60 minutes), they are not suitable for
therapy "on demand" (for relief of pain, heartburn).
All PPIs reduce basal and stimulated gastric
secretion regardless of the nature of the stimulus.
Pharmacokinetics.
Indications for use:
Proton pump inhibitors - drugstreatment of choice
acid-associated diseases such as:
gastroesophageal reflux disease (GERD,
reflux esophagitis, non-erosive GERD),
stomach and duodenal ulcer (DUD),
symptomatic ulcers (Zollinger–
Allison, etc.)
functional dyspepsia,
Helicobacter pylori infection.
Drug interactions with proton pump inhibitors.
Side effects.
The incidence and severity of side effects,caused by PPIs is generally low (up to 3-5%), especially when
short courses of treatment (up to 3 months).
Contraindications for taking PPIs:
1. Increased sensitivity of the patient to theircomponents.
2. Children's age up to 14 years (since children in this
time goes on the formation of the work of organs
internal secretion, and any intervention
may result in serious failure).
3. In pregnant women, PPIs are used according to strict
indications (category of action on the fetus - B),
4. Nursing mothers for the period of treatment
advised to stop breastfeeding
feeding.
H2-histamine blockers
I generation:Cimetidine (Tagamet).
II generation:
Ranitidine (Zantac).
Nizatidine (Axid).
Roxatidine (Roxan).
III generation:
Famotidine (Kvamatel).
Combined: Ranitidine-bismuth citrate
(pyloride).
Pharmacodynamics.
H2-histamine blockers (H2-HB) competitively inhibit the actionhistamine to H2-histamine receptors of parietal and main
cells, suppressing basal and stimulated secretion.
In this case, there is a decrease in the production of HC1 and pepsinogen without
concomitant reduction in mucus and bicarbonate production.
Gastrin production is suppressed slightly, pronounced
inhibition is possible only at high doses and prolonged
treatment.
Under the influence of certain H2-HB (ranitidine, famotidine)
increases the formation of prostaglandin (Pg) E2 in the mucosa
membrane of the stomach and duodenum, which mediates their
cytoprotective and indirect reparative effect.
In addition, the ability of ranitidine to increase the tone
lower esophageal sphincter, which is especially important for eliminating
heartburn.
Representatives of all three generations of H2-HB have a direct
antioxidant action, both due to the blockade of the formation
hypochloric acid and hydroxyl radical, and due to
increase in the activity of superoxide dismutase - the most important
antioxidant enzyme.
Main differences between generations of H2-GB
Pharmacokinetics.
Indications for the use of H2-histamine blockers:
Indications for the use of H2histamine blockers:ulcerative lesions of the esophageal mucosa;
gastroesophageal reflux with and without esophagitis;
peptic ulcer of the stomach and duodenum;
symptomatic and medicinal, acute and chronic ulcers
stomach and duodenum;
chronic dyspepsia with epigastric and retrosternal pain;
Zollinger-Ellison syndrome;
systemic mastocytosis;
Mendelssohn's syndrome;
prevention of stress ulcers;
prevention of aspiration pneumonia;
bleeding from the upper gastrointestinal tract;
pancreatitis.
Contraindications:
Contraindications:hypersensitivity to this drug
groups;
cirrhosis of the liver with portosystemic
encephalopathy in history;
dysfunction of the liver and kidneys;
pregnancy;
lactation;
children's age (up to 14 years).
Side effects.
Side effects associated with the relative selectivity of blockade of histamine H2 receptors and / or effects on H2-histamine receptorsother organs:
From the side of the central nervous system: headache, dizziness, confusion.
From the side of the CCC: arrhythmia, conduction, hypotension (occur rarely, but
the risk increases significantly in the elderly and those with cardiovascular diseases).
From the respiratory system: bronchospasm (most often caused
cimetidine).
From the immune system: autoimmune interstitial nephritis (most
often induced by cimetidine).
From the blood system: leukopenia, thrombocytopenia, aplastic anemia,
pancytopenia.
Side effects associated with competition for binding sites and metabolism
sex hormones (most commonly caused by cimetidine): reversible
gynecomastia, impotence
Side effects associated with exposure to the gastrointestinal tract:
On the part of the intestine: diarrhea, constipation (dose-dependent effects).
On the part of the liver: increased transaminases, hepatitis (develop approximately after
month, more often in patients older than 50 years. Most often caused by ranitidine,
cimetidine).
Side effects due to long-term use of drugs:
Recoil syndrome (for prevention, the dose of the drug upon withdrawal is first reduced in
2 times a week and only then canceled completely).
Receptor escape syndrome (requires changing antisecretory drug or
dose increase).
Main pharmacokinetic interactions of H2-histamine blockers
Main pharmacokinetic interactions of H2 histamine blockers One of the best H2-GB can be calledfamotidine, which has a number of
advantages over others
drugs in this group:
- The highest activity.
- Sufficiently long-term.
– Minimal side effects and
the greatest safety in the long term
application.
– Lack of interaction with the system
cytochrome P-450.
– Availability of dosage forms for oral
and parenteral use.
– Relatively low cost.
List of used literature
Clinical pharmacology.: textbook for universities / Ed. V.G.Kukesa. - 4th edition., Revised. and additional, - 2009. - 1056 p.
Clinical pharmacology: selected lectures / S.V. shackled,
V.V. Gaivoronskaya, A.N. Kulikov, S.N. Shulenin. - 2009. - 608 p.
Belousov Yu. B. Clinical pharmacology and pharmacotherapy:
guide for doctors. - 2nd ed., stereotypical / Yu. B.
Belousov, V. S. Moiseev, V. K. Lepakhin. - M.: Universum
Publishing, 2000. - 539 p.
Pharmacology: textbook. - 10th ed., corrected, revised. and additional Kharkevich D. A. 2010. - 752 p.
Isakov V.A. Proton pump inhibitors: their properties and
application in gastroenterology / V. A. Isakov. - M.:
Academic book, 2001. - 304 p.
Lapina T.P. Proton pump inhibitors: from
pharmacological properties for clinical practice / T. P.
Lapina // Farmateka. - 2002. - S. 3-8.
Khomeriki S. G. Hidden aspects of the clinical use of H2 blockers / S. G. Khomeriki, N. M. Khomeriki // Farmateka. 2002. - S. 9-15.
With the development of the pharmaceutical industry for the treatment of:
- - erosive-destructive diseases of the gastroduodenal zone,
- -gastroesophageal reflux disease (GERD)
- - with the development of reflux esophagitis,
- -pathology associated with Hp infection,
in adults, a wide range of proton pump inhibitors are offered as initial therapy and the "gold standard"
Essence and chemical classification of antisecretory drugs
Antisecretory agents inhibit the secretion of hydrochloric acid and pepsin. The synthesis of hydrochloric acid is controlled by three types of receptors:
- -H-2-histamine,
- - gastrinic
- - M-cholinergic receptors.
Thus, 4 groups of antisecretory drugs are distinguished:
- - blockers of H-2-histamine receptors,
- - m-cholinolytics,
- - proton pump inhibitors
- - blockers of gastrin receptors.
Mechanism of action, antisecretory drugs
H2-blockers in the treatment of chronic gastritis and peptic ulcer have been used since the mid-70s and are currently one of the most common antiulcer drugs.
The main antisecretory effect of H2-blockers is manifested as a result of blocking H2-histamine receptors in the gastric mucosa. Due to this, the production of hydrochloric acid is suppressed and an antiulcer effect is carried out. The drugs of new generations differ from the first drug of the cimetidine group in the degree of suppression of the nocturnal and total daily secretion of hydrochloric acid, as well as the duration of the antisecretory effect. (see table No. 2 in the appendix)
Drugs vary in bioavailability values:
- - cimetidine has a value of -60-80%,
- - ranitidine - 50-60%,
- - famotidine - 30-50%,
- -nizatidine - 70%,
- -roxatidine - 90-100%.
Removal of drugs is carried out by the kidneys, and 50-90% of the dose taken is unchanged. The duration of the half-life is different for the drugs of the group: cimetidine, ranitidine and nizatidine for 2 hours, famotidine - 3.5 hours, roxatidine - 6 hours.
CIMETIDIN (Russia)
Dosage form
tablets 200mg
Pharmacotherapeutic group
H2-histamine receptor blockers and similar drugs
Indications for use:
- - peptic ulcer of the stomach and duodenum,
- - hyperacidity of gastric juice (reflux esophagitis, gastritis, duodenitis),
- Zollinger-Ellison syndrome
- - pancreatitis,
- - gastrointestinal bleeding.
Contraindications
- - hepatic and / or renal insufficiency,
- -pregnancy, breastfeeding
- -Children and adolescents (up to 14 years).
Side effects
- -deterioration of the excretory function of the liver,
- -decreased absorption of vitamin B12,
- -neutro- and thrombocytopenia,
- - allergic reactions (skin rashes).
In the treatment of chronic gastritis, 4 drugs of the group are most often used.
RANITIDIN (India)
Release form
10 tab. in aluminum strips. 1, 2, 3, 4, 5 or 10 strips in a carton box. (150-300mg)
- - Blocker of H-2 receptors of the 2nd generation,
- - Compared with cematidine, it has 5 times greater antisecretory activity,
- - Acts longer - up to 12 hours.
Virtually no side effects
Rare: headache,
Nausea,
Tablets of 150 mg are taken 1 time in the morning after meals and 1-2 tablets in the evening before bedtime. Other regimens are possible - 1 tablet 2 times a day or 2 tablets 1 time at night. Treatment must be continued for several months or years, maintenance dose - 1 tablet at night.
Contraindications:
- - pregnancy;
- - lactation;
- - children's age up to 12 years;
- - hypersensitivity to ranitidine or other components of the drug.
FAMOTIDIN (Serbia)
Tablets of 20 mg and 40 mg, ampoules of 20 mg.
- - Blocker of H2 receptors of the 3rd generation,
- - Antisecretory effect exceeds ranitidine by 30 times.
- - In case of complicated peptic ulcers, 20 mg in the morning and 20-40 mg in the evening before bedtime are prescribed. It is possible to take only 40 mg at bedtime for 4-6 weeks, maintenance therapy - 20 mg once at night for 6 weeks.
Side effects
- -dry mouth
- - headache
- - allergic reactions
- - sweating
Contraindications:
- - pregnancy;
- - lactation period;
- - children's age up to 3 years with a body weight of less than 20 kg (for this dosage form);
- - hypersensitivity to famotidine and other blockers of histamine H2 receptors.
NIZITIDIN (Russia)
Release form. Capsules of 0.15 and 0.3 g in packs of 30 pieces; concentrate for infusion in vials of 4, 6 and 12 ml (1 ml contains 0.025 g of nizatidine).
- - 4th generation blocker.
- - Assign tablets of 150 mg 2 times a day or 2 tablets at night for a long time.
- - Gastroduodenal ulcers heal within 4-6 weeks in 90% of patients.
Side effect.
- -possible nausea
- -rarely - damage to the liver tissue;
- -drowsiness,
- - sweating,
Contraindications. Hypersensitivity to the drug.
ROXATIDINE (India)
Release form:
Roxatidine Precautions
Before starting treatment, it is necessary to exclude the presence of malignant tumors in the gastrointestinal tract.
- -H2-blocker of the 5th generation.
- - Tablets of 150 mg are prescribed 1 time per day or 2 tablets 1 time at night.
Contraindications:
- - hypersensitivity,
- - impaired liver and kidney function,
- -pregnancy, breastfeeding (should be discontinued for the period of treatment),
- -childhood.
Side effects:
- -headache
- - blurred vision
- -constipation
- - gynecomastia,
- - impotence, transient decrease in libido,
- - skin rash, itching.
Proton pump inhibitors (PPI) play a major role in the treatment of chronic gastritis and peptic ulcer disease.
(fig. No. 1 see in the appendix)
The high therapeutic efficacy of proton pump inhibitors is explained by their pronounced antisecretory activity, which is 2-10 times higher than that of H2-blockers. Taking an average therapeutic dose once a day (regardless of the time of day) suppresses the level of gastric acid secretion during the day by 80-98%, and for H2-blockers, the same indicator is 55-70%.
Ingestion of PPIs promotes entry into the acidic environment of the stomach, sometimes causing premature conversion to sulphenamides, which are poorly absorbed in the gut. Therefore, they are used in capsules that are resistant to the action of gastric juice.
The half-life of omeprazole is 60 minutes, pantoprazole is eliminated in 80-90 minutes, and lansoprazole is 90-120 minutes. Diseases of the liver and kidneys do not significantly affect these indicators.
Omeprazole, Pantoprazole (see above in diagnosis and treatment).
LANSOPROZOL (Russia)
Release form
Lansoprazole 30mg caps N30
pharmachologic effect
Anti-ulcer agent.
Take orally 30 mg 1 time per day (morning or evening). With anti-Helicobacter therapy, the dose is increased to 60 mg per day.
Side effects:
- -allergic reaction
- -headache
- -photosensitization
Contraindications:
- - Hypersensitivity,
- - malignant neoplasms of the gastrointestinal tract,
- - pregnancy (especially the first trimester)
M-cholinolytics are the oldest means. the first of them for the treatment of peptic ulcers used preparations of belladonna and atropine. For a long time, atropine was considered as the main medicine for chronic gastritis and peptic ulcers. However, the pharmacodynamics of drugs is manifested in an indiscriminate effect on numerous M-cholinergic receptors in the body, which leads to the development of many serious side effects. Among the group of M-anticholinergic drugs, the selective M1-anticholinergic pirenzepine is the most effective, blocking M1-cholinergic receptors at the level of intramural ganglia and inhibiting. the influence of the vagus nerve on the secretion of hydrochloric acid and pepsin, without having an inhibitory effect on the M-cholinergic receptors of the salivary glands, heart and other organs.
Pirenzepine is the only one included in group A02B (ATX code A02BX03), however, in terms of clinical efficacy, it is inferior to both proton pump inhibitors and H2 blockers. Therefore, its use in modern therapy is limited.
PIRENZEPIN (Germany)
Forms of release and composition:
Pirenzepine tablets of 0.025 and 0.05 g - in a package of 50 pcs.
Powder Pirenzepine 0.01 g in an ampoule - in a package of 5 ampoules with a solvent.
Pharmacological group
M-anticholinergic.
(after 2-3 days) switch to oral administration.
Substance use:
- - peptic ulcer of the stomach and duodenum chronic - hyperacid reflux esophagitis;
- - erosive and ulcerative lesions of the gastrointestinal tract, incl. caused by antirheumatic and anti-inflammatory drugs;
- - stress ulcers of the gastrointestinal tract;
- - Zollinger-Ellison syndrome;
- - bleeding from erosions and ulcerations in the upper gastrointestinal tract.
Contraindications
Hypersensitivity.
Application restrictions
Glaucoma, prostatic hyperplasia, tachycardia.
Side effects of the substance Pirenzepine
Dry mouth
- - paresis of accommodation,
- - diarrhea,
- - allergic reactions.
Dosage and administration
Inside, in / m, in / in. Inside - 50 mg in the morning and evening 30 minutes before meals with a small amount of water. The course of treatment is at least 4 weeks (4-8 weeks) without interruption.
In severe forms of peptic ulcer of the stomach and duodenum, it is administered intramuscularly and intravenously, 10 mg every 8-12 hours.
In the course of many years of searching for inhibitors of gastrin receptors and creating a number of drugs of this type, there were many difficulties, and their widespread use in practical medical therapy has not yet begun. A non-selective blocker of gastrin receptors is proglumide (code A02BX06). The clinical effect is consistent with the first generation of H2-blockers, but the drug has the advantage of a small number of side effects.
In the Russian Federation, gastrin receptor blockers are not registered.
