Agents that block H2-histamine receptors. Why do we need drugs that block histamine H2 receptors? Histamine H2 receptor blockers are used to treat

H2 blockers histamine receptors (English) H2-receptor antagonists) - medicines intended for the treatment of acid-dependent diseases of the gastrointestinal tract. The mechanism of action of H2 blockers is based on the blocking of H2 receptors (also called histamine) on the parietal cells of the gastric mucosa and, for this reason, reducing the production and entry of hydrochloric acid into the gastric lumen. They belong to antiulcer antisecretory drugs.

Types of H2 blockers

A02BA H2-histamine receptor blockers
A02BA01 Cimetidine
A02BA02 Ranitidine
A02BA03 Famotidine
A02BA04 Nizatidine
A02BA05 Niperotidine
A02BA06 Roxatidine
A02BA07 Ranitidine bismuth citrate
A02BA08 Lafutidine
A02BA51 Cimetidine and other drugs
A02BA53 Famotidine and other drugs

Government Decree Russian Federation dated December 30, 2009 No. 2135-r, the following H2-histamine receptor blockers are included in the List of Vital and Essential Medicines:

• ranitidine - solution for intravenous and intramuscular injection; injection; coated tablets; film-coated tablets
• famotidine - lyophilizate for the preparation of a solution for intravenous administration; coated tablets; film-coated tablets.

From the history of H2 blockers of histamine receptors

In the treatment of patients with ulcerative gastroduodenal bleeding, the use of H 2 -blockers is not recommended, the use of proton pump inhibitors is preferable (Russian Society of Surgeons).

Resistance to H 2 blockers

Comparative characteristics of H2 blockers

Comparative characteristics of H2-blockers (Kornienko E.A., Fadina S.A.):

H2 blockers and Clostridium difficile associated diarrhea

Professional medical articles dealing with the treatment of gastrointestinal diseases with H2-blockers of histamine receptors

• Alekseenko S.A., Loginov A.F., Maksimova I.D. The use of small doses of H2 blockers of the III generation in the treatment of dyspepsia // Consilium-Medicum. - 2005. - Volume 7. - No. 2.


• Okhlobystin A.V. The use of histamine H2 receptor blockers in gastroenterology // RMJ. Diseases of the digestive system. - 2002. - V.4. - No. 1.


• Trade names of H2 blockers In Russia, the following H2-blockers of histamine receptors are registered (were registered):
  • active substance cimetidine: Altramet, Apo-Cimetidine, Belomet, Histodil, Yenametidine, Neutronorm, Novo-Cimetin, Primamet, Simesan, Tagamet, Ulkuzal, Ulcometin, Cemidin, Cygamet, Cimehexal, Cymedin, Cymet, Cimetidine, Cimetidine Lannacher, Cimetidine-Rivofarm
  • active substance ranitidine: Asitek, Acidex, Acilok, Vero-Ranitidine, Gistak, Zantak, Zantin, Zoran, Raniberl 150, Ranigast, Ranisan, Ranison, Ranitidine, Ranitidine Vramed, Ranitidine SEDIKO, Ranitidine-AKOS, Ranitidine-Acri, Ranitidine-BMS, Ranitidine-ratiopharm , Ranitidine-Ferein, Ranitidine hydrochloride, Ranitidine coated tablets, Ranitin, Rantag, Rantak, Renks, Ulkodin, Ulran, Yazitin
  • active substance famotidine: Antodin, Blockacid, Gasterogen, Gastrosidin, Kvamatel, Kvamatel mini, Lecedil, Pepsidin, Ulfamid, Ulceran, Famonit, Famopsin, Famosan, Famotel, Famotidine, Famotidine-ICN, Famotidine-AKOS, Famotidine-Akri, Famotidine-Apo, Famocid
  • active substance nizatidine: Aksid
  • active substance roxatidine: Roxane
  • active substance ranitidine bismuth citrate: Pyloride
  Medicines with active substance niperotidine And lafutidine not registered in Russia.
  
  The following brands of H2 blockers are registered in the US:
  

  In Japan, in addition to the "conventional", drugs are registered with active substance lafutidine: Protecadin and Stogar.

H2 - receptors localized mainly in the gastric mucosa on the parietal cells that produce hydrochloric acid, and the main (synonym: zymogen) cells that produce enzymes of gastric juice. H2 receptors are also located on cardiomyocytes and pacemaker cells in the heart, in blood cells and on mast cell membranes. Excitation of histamine H2 receptors stimulates all digestive, salivary, gastric and pancreatic glands, as well as bile secretion. Histamine speeds up and strengthens heart contractions, and also regulates its release from mast cells (self-regulation). To the greatest extent, histamine stimulates the parietal cells of the stomach. The formation of free ions of chlorine and hydrogen (the formation of hydrochloric acid) in these cells is stimulated by carbonic anhydrase, which is activated in them with the participation of cAMP. H2 receptor blockers inhibit the activity of adenylate cyclase in these cells, thereby reducing the content of cAMP in them.

The main effects of the action of H2 blockers - receptors:

● decrease in all types of secretion of hydrochloric acid in the stomach: basal, nocturnal and stimulated (for example, histamine, gastrin, insulin, ACH, caffeine, food intake, stretching of the fundus of the stomach, etc.);

● decrease in the synthesis of pepsin (the main proteolytic enzyme of gastric juice);

● decrease in motor activity of the stomach, decrease in the amplitude of contraction of its antrum with a slowdown passage(promotion) of gastric contents;

● negative foreign - and chronotropic effect, positive dromotropic effect (decrease in the time of atrioventricular conduction - the risk of arrhythmias).

● increased synthesis in the gastric mucosa and duodenum prostaglandin E2 (PGE2) with gastroprotective activity.

PGE2 increases the secretion of mucus and bicarbonates, inhibits the formation of hydrochloric acid, increases the rate of replication (recovery) of mucosal cells, improves blood flow in the vessels of the gastric mucosa. Maintaining adequate blood flow not only ensures the delivery of oxygen to the tissues and nutrients, but also allows you to remove hydrogen ions that easily penetrate from the lumen of the stomach into damaged or ischemic mucosal tissues.

Cyclooxygenases (COX) Types 1 and 2 are enzymes involved in the formation of prostaglandins from arachidonic acid (see Scheme 5 on page 63). GCS and NSAIDs of the first generation, reducing the activity of COX, disrupt the synthesis PGE2, which determines their ulcerogenicity. Second-generation NSAIDs (meloxicam, nimesulide, celecoxib, rofecoxib) selectively inhibit only COX-2 responsible for the synthesis PGE1(activator of inflammatory mediators), and do not affect COX-1 involved in the synthesis PGE2.

There are three generations of H2 receptor blockers ("-tidinov"):

● the first generation includes cimetidine (gistodil);

● to the second - ranitidine (Zantak, Ranigast, Ranisan, Rantak, Gistak);

● to the third - famotidine (kvamatel, famosan).

In first generation drugs, the affinity is significantly lower than in drugs of the 2nd, and even more so of the 3rd generation. This makes it possible to prescribe the latter in much smaller doses. In addition, famotidine is practically not biotransformed in the liver.

The drugs are prescribed orally or administered intravenously (drip or bolus for gastrointestinal bleeding from erosions or ulcers of the mucous membrane that have arisen against the background of stress reactions: severe burns, multiple injuries, sepsis, etc.).

Cimetidine is an inhibitor of microsomal liver enzymes and, while taking it, the appointment of BAB, indirect anticoagulants, tranquilizers, PDE inhibitors is contraindicated (danger of their cumulation). The combined use of antacid drugs and H2 receptor blockers is undesirable due to malabsorption of the latter. Their combination with M - anticholinergic - pirenzepine is rational. Currently, in addition to the traditional method of using H2-receptor blockers (cimetidine 1 tablet 4 times a day, ranitidine 1 tablet 2 times a day), a single daily dose of the drug is used in the evening at 20.00.

Unwanted Effects(more common with cimetidine) :

● all drugs penetrate the BBB: it is possible (especially in children under 1 year old and geriatric patients) the appearance of disorientation, dysarthria (pronunciation difficulties), hallucinations, convulsions;

● on the part of the gastrointestinal tract, anorexia (loss of appetite), diarrhea, constipation are possible.

● at short-term rates, there may be headache, myalgia, skin rash.

● binding to H2 - receptors on the surface of blood cells, drugs can cause leukopenia, thrombocytopenia, autoimmune hemolytic anemia.

●with fast intravenous administration large doses of these drugs may cause a cardiotoxic effect (bradycardia, hypotension, arrhythmias);

● drugs increase the synthesis of histamine (due to the activation of histidine decarboxylase) and its release from mast cells (due to the blockade of H2 receptors on mast cells). As a result, the condition of patients with bronchial asthma may worsen, the course of lupus erythematosus may worsen.

Cimetidine blocks androgen receptors, which in some cases leads to a decrease in sperm count and impotence. If the drug is prescribed to a woman during pregnancy, then this can lead to the birth of a child with adrenogenital syndrome. Cimetidine reduces the secretion of gonadotropic hormones and increases the level of prolactin, causing gynecomastia, galactorrhea (spontaneous flow of milk from the mammary glands out of connection with the process of feeding the child), macromastia (abnormal enlargement of the mammary glands), cliteromegaly and delayed sexual development of boys.

Abrupt discontinuation of H2 blockers - histamine receptors, can lead to a withdrawal syndrome. The appearance of the latter is associated with hypergastrinemia, which occurs in response to the suppression of the acidity of the content, as well as with adaptive reactions in the form of a change in the density (number) of receptors or their affinity for histamine. Therefore, it is important to follow a gradual dose reduction regimen for H2 antagonists - receptors when they are canceled and use pharmacological protection by taking other antisecretory agents.

Currently, new drugs are entering medical practice: nizatidine (axid, nizax), roxatidine (altat) and others. They have even more activity than famotidine, and do not cause withdrawal syndrome and AEs from the heart, SMC of the gastrointestinal tract and blood.

8.3. H+-, K+-ATPase inhibitors

(proton pump inhibitors)

H + -, K + - ATPase is an enzyme that catalyzes (stimulates) the work proton pump (pump) parietal cells. The proton pump is an enzymatic protein on the membrane of the secretory tubules of cells, which, in response to stimulation of membrane receptors (cholinergic, gastrin or histamine), transfers protons (hydrogen ions) from the cell to the gastric lumen in exchange for potassium ions. proton pump inhibitors (IPP or proton pump - IPN) omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, etc. "-prazoles", inhibiting H + -, K + - ATPase, interrupt the final phase of the secretion of hydrochloric acid. To restore the ability to secrete hydrochloric acid, the parietal cell is forced to synthesize a new enzyme protein, which takes about 18 hours.

PPIs are prodrugs and turn into inhibitors only when the pH of the gastric juice is acidic (at a pH of no more than 4), that is, they maintain acidity during the day within the limits favorable for the healing of a stomach or duodenal ulcer. Once activated, they interact with SH groups(cysteine ​​amino acids) H + -, K + - ATPase, firmly blocking its function.

PPIs intensively and for a long time suppress all types of hydrochloric secretion. They are effective even when it is impossible to suppress the secretion of hydrochloric acid with the help of M-anticholinergics or H2-receptor blockers. The drugs also disrupt the work of the proton pump in H. Pylori, which determines their bacteriostatic effect. Intravenous preparations are administered for venous bleeding from ulcers and erosions.

These drugs are acid-resistant and poorly absorbed when exposed to an acidic environment. Therefore, per os they are taken in the form of acid-resistant capsules or they are taken in the form of a suspension with alkaline solutions.

When using PPIs, the concentration of gastrin in the blood increases compensatory, i.e., with a sharp withdrawal of drugs, a withdrawal syndrome is possible.

Histamine is one of the hormones vital for a person. It performs the functions of a kind of "watchman" and comes into play under certain circumstances: physical activity, injuries, illnesses, ingestion of allergens, etc. The hormone redistributes the blood flow in such a way as to minimize possible damage. At first glance, the work of histamine should not harm a person, but there are situations when a large amount of this hormone brings more evil than good. In such cases, doctors prescribe special drugs (blockers) in order to prevent the histamine receptors of one of the groups (H1, H2, H3) from starting to work.

Why do you need histamine?

Histamine is a biologically active compound involved in all major metabolic processes in the body. It is formed from the breakdown of an amino acid called histidine and is responsible for the transmission of nerve impulses between cells.

Normally, histamine is in an inactive state, but at dangerous times associated with illness, injury, burns, the intake of toxins or allergens, the level of free hormone increases sharply. In the unbound state, histamine causes:

• spasms of smooth muscles;
• lowering blood pressure;
• expansion of capillaries;
• increased heart rate;
• increased production of gastric juice.

Under the action of the hormone, the secretion of gastric juice and adrenaline increases, tissue edema occurs. Gastric juice is a rather aggressive medium with high acidity. Acid and enzymes not only help digest food, they are able to act as an antiseptic - to kill bacteria that enter the body at the same time as eating.

The “management” of the process occurs with the help of a central nervous system and humoral regulation (control by hormones). One of the mechanisms of this regulation is triggered through special receptors - specialized cells that are responsible, among other things, for the concentration of hydrochloric acid in gastric juice.

Histamine receptors

Certain receptors called histamine (H) respond to the production of histamine. Doctors divide these receptors into three groups: H1, H2, H3. As a result of excitation of H2 receptors:

• the functioning of the gastric glands is enhanced;
• the tone of the muscles of the intestine and blood vessels increases;
• allergies and immune reactions appear;

Blockers of H2 histamine receptors act only partially on the mechanism of release of hydrochloric acid. They reduce the production caused by the hormone, but do not stop it completely.

Important! High acid content in gastric juice is a threatening factor in some diseases of the gastrointestinal tract.

What are blocker drugs?

These drugs are designed to treat diseases of the gastrointestinal tract, in which a high concentration of hydrochloric acid in the stomach is dangerous. They belong to drugs against peptic ulcer, which reduce secretion, i.e., are designed to reduce the flow of acid into the stomach.

Blockers of the H2 group have various active ingredients:

• cimetidine (Histodil, Altamet, Cimetidine);
• nizatidine (Axid);
• roxatidine (Roxane);
• famotidine (Gastrosidin, Kvamatel, Ulfamid, Famotidine);
• ranitidine (Gistak, Zantak, Rinisan, Ranitiddin);
• ranitidine bismuth citrate (Pyloride).

Funds are issued in the form of:

• ready-made solutions for intravenous or intramuscular administration;
• powder for solution preparation;
• tablets.

To date, cimetidine is not recommended for use due to a large number of side effects, including a decrease in potency and an increase in mammary glands in men, the development of pain in the joints and muscles, an increase in the level of creatinine, changes in the composition of the blood, damage to the central nervous system, etc.

Ranitidine has far fewer side effects, but it is less and less used in medical practice, as next-generation drugs (Famotidine) are coming to replace, whose effectiveness is much higher, and the duration of action is several hours longer (from 12 to 24 hours).

Important! In 1–1.5% of cases, patients experience resistance to blocker drugs.

When are blockers prescribed?

An increase in the level of acid in the gastric juice is dangerous when:

• stomach or duodenal ulcer;
• inflammation of the esophagus when the contents of the stomach are thrown into the esophagus;
• benign tumor of the pancreas in combination with a stomach ulcer;
• reception for the prevention of the development of peptic ulcer during long-term therapy of other diseases.

The specific drug, doses and duration of the course are selected individually. Cancellation of the drug should be gradual, as with a sharp end of the reception, side effects are possible.

Disadvantages of histamine blockers

H2 blockers affect the production of free histamine, thereby reducing the acidity of the stomach. But these drugs do not act on other stimulants of acid synthesis - gastrin and acetylcholine, that is, these drugs do not give complete control over the level of hydrochloric acid. This is one of the reasons why doctors consider them relatively outdated remedies. Nevertheless, there are situations when the appointment of blockers is justified.

There is a rather serious side effect of therapy using H2 histamine receptor blockers - the so-called "acid rebound". It lies in the fact that after the withdrawal of the drug or the end of its action, the stomach seeks to "catch up", and its cells increase the production of hydrochloric acid. As a result, after a certain period of time after taking the medicine, the acidity of the stomach begins to rise, causing an exacerbation of the disease.

Another side effect- diarrhea caused by the pathogen Clostridium. If, together with the blocker, the patient takes antibiotics, then the risk of diarrhea increases tenfold.

Modern analogues of blockers

New drugs are coming to replace blockers - but they cannot always be used in treatment due to the genetic or other characteristics of the patient or for economic reasons. One of the obstacles to the use of inhibitors is the fairly common resistance (resistance to the drug).

H2-blockers differ from proton pump inhibitors for the worse in that their effectiveness decreases with a repeated course of treatment. Therefore, long-term therapy involves the use of inhibitors, and H-2 blockers are sufficient for short-term treatment.

Only a doctor has the right to make a decision on the choice of drugs based on the patient's history and research results. Patients with gastric or duodenal ulcers, especially in the chronic course of the disease or at the first appearance of symptoms, need to individually select acid-suppressing agents.

CHAPTER 20

20.1. MEDICINES REDUCING ACID-PEPTIC FACTOR ACTIVITY

In the development and recurrence of diseases associated with damage to the mucous membranes of the stomach and duodenum, the role of factors (acid-peptic, infectious (Helicobacter pylori), motor disorders), which can be influenced by drugs. In 1910, the position “no acid, no ulcer” was formulated, and this old Schwartz rule has not lost its relevance to the present. However, the aggressiveness of gastric juice is physiological, and the normal mucous membrane of the stomach and duodenum is resistant to its effects. Hydrochloric acid provides activation of pepsinogen, creates the pH level necessary for the functioning of gastric proteases, promotes the swelling of food protein colloids, participates in the regulation of secretion and motility of the stomach, gallbladder, and has bactericidal properties. Hypersecretion of hydrochloric acid is considered as the main pathophysiological mechanism of mucosal damage, and the process of back diffusion of hydrogen ions is called the key to reducing its resistance. Aggressive factors also include pepsin, bile acids, and acceleration of gastric emptying.

The element of the mucous membrane responsible for the secretion of hydrochloric acid is the parietal (parietal) cell. On its apical membrane there is an enzyme that promotes the exchange of protons in the cytoplasm for potassium ions (K +) with the release of the former into the environment. This so-called proton pump functions with the participation of cAMP, calcium ions (Ca 2 +) and in the presence of potassium ions localized in the lumen of the secretory tubules. Enzyme activation begins with the reaction of receptors (located on the basement membrane) to specific chemostimulants and transmembrane signal transmission to H + /K + -ATPase (proton pump). The existence of three clinically significant types of receptors has been proven: acetylcholine, histamine and gastrin.

The parietal cell contains H 2 -histamine receptors, m 3 - muscarinic receptors and gastrin receptors. The gastrin receptor is referred to as the B receptor for cholecystokinin. As a result of the activation of parietal cells under the action of both gastrin and acetylcholine, an increase in the intracellular concentration of Ca 2+ and phosphorylation of target proteins under the action of protein kinase C can occur. resulting in an increase in the content of intracellular cAMP. After that, there is an increase in the intracellular concentration of Ca 2+ (they enter the cell through the plasma membrane).

The signal from the H 2 -histamine receptor is transmitted through cAMP-dependent pathways. Cholinergic and gastrinergic influences are carried out through Ca 2+ -dependent processes (the system of phosphatidylinositol-inositol triphosphate diacylglycerol). The final link in these processes is the proton pump, which has K + , H + -ATPase activity and promotes the excretion of hydrogen ions into the lumen of the stomach.

Through clinical studies, it has been established that there is a direct relationship between ulcer healing and the ability of drugs to suppress acidity. That is why in diseases in the pathogenesis of which an increase in gastric secretion of hydrochloric acid is a trigger for damage to the mucous membrane, the management of acid production is the most important task of drug therapy.

The "evolution" of drugs that reduce the influence of the acid-peptic factor has come from the creation of antacids, blockers of m-choline and H 2 -histamine receptors to the appearance of proton pump inhibitors, resulting in an increase in the efficiency, selectivity, and, consequently, the safety of the drug used. pharmacotherapy.

Antacids

Antacids - medicines that reduce the content of already released hydrochloric acid in the stomach (anti- against, acidum- acid). According to B.E. Votchala, "alkalis sweep the stomach."

Requirements for antacids:

The most rapid interaction with hydrochloric acid located in the lumen of the stomach to relieve pain, heartburn, discomfort, eliminate pylorus spasm, normalize motor

rickets of the stomach and the cessation of the acid "release" into the initial sections of the duodenum;

The ability to neutralize a significant amount of hydrochloric acid in gastric juice, i.e. have a large acid (buffer) capacity;

The ability to maintain the state of the stomach environment at pH 4-5 (at the same time, the concentration of H + decreases by 2-3 orders of magnitude, which is sufficient to suppress the proteolytic activity of gastric juice);

Security;

Economic accessibility;

Good organoleptic properties.

Classification

Antacids are divided into:

systemic And non-systemic(local action). The former are able to increase the alkalinity of the blood plasma, the latter do not affect the acid-base state;

anionic(sodium bicarbonate, calcium carbonate) and cationic(gels of aluminum and magnesium hydroxides);

neutralizing And neutralizing-enveloping-adsorbing[aluminum hydroxide*, magnesium trisilicate, almagel*, aluminum phosphate (phosphalugel*), etc.].

Systemic antacids(sodium bicarbonate, sodium citrate), quickly reacting with hydrochloric acid of the stomach, neutralize it and thereby help to reduce the peptic activity of gastric juice, eliminate the direct irritating effect on the mucous membrane of the stomach and duodenum.

Non-systemic antacids. These include: magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium trisilicate, aluminum hydroxide *, aluminum phosphate (phosphalugel *), rarely - precipitated calcium carbonate *, calcium carbonate, calcium phosphate, bismuth carbonate, etc.

The drugs of this group are insoluble in water and are poorly adsorbed. In the process of neutralization of gastric juice, hydrochloric salts are formed, which, reacting with carbonate of intestinal juice and pancreatic juice, form hydroxide or carbonate of the original salt. Thus, the body does not lose either cations (H +) or anions (HCO3 -) and there is no change in the acid-base state.

Properties of Al-containing antacids:

Antipeptic ability;

Enhance the synthesis of prostaglandins;

Adsorb bile acids, pepsin, lysolecithin, toxins, gases, bacteria;

Weaken motor skills;

Increase the tone of the lower esophageal sphincter. Properties of Mg-containing antacids:

Antipeptic ability;

Astringent properties, form a protective coating;

Prevent the release of pepsin;

Enhance mucus formation;

Strengthen motor skills;

Strengthen the resistance of the gastric mucosa.

Some preparations contain both aluminum hydroxide (Al) and magnesium hydroxide (Mg). Mg hydroxide and Al hydroxide are able to form a protective film on the damaged tissue, enhancing the protective capabilities of the mucous membrane of the gastroduodenal zone, and contribute to a qualitative improvement in scarring processes. Al salts cause constipation, and Mg salts have a slight laxative effect. Mg hydroxide provides a quick onset, while Al hydroxide provides a long-lasting effect. Mg hydroxide prevents the release of pepsin, and Al hydroxide adsorbs pepsin, bile salts, isolecithin, has a cytoprotective effect by increasing the secretion of prostaglandins (PgE 2), increases the tone of the lower esophageal sphincter. The composition of non-systemic antacids is presented in table. 20-1.

Table 20-1. Combined non-systemic antacids

Indications for the use of antacids:

Autumn-spring prevention of peptic ulcer of the stomach and duodenum;

Treatment of patients with peptic ulcer, gastroesophageal reflux, peptic ulcers of the esophagus, non-ulcer dyspepsia, gastritis with increased secretion, duodenitis, symptomatic peptic ulcers of the stomach or duodenum;

Discomfort and pain in the epigastrium, heartburn, sour belching after errors in the diet, excessive alcohol consumption, taking medications;

Prevention of gastrointestinal bleeding long-term treatment NSAIDs, glucocorticoids and some other drugs;

Elimination of pyloric hypertonicity syndromes with a sharp increase in the volume of gastric secretion;

Prevention of "stress" ulcers in intensive care;

functional diarrhea. Dosing regimen

The effectiveness of antacids is measured by the number of milliequivalents of hydrochloric acid neutralized by the so-called standard dose. Usually this is 1 g of solid and 5 ml of liquid dosage form - an amount capable of maintaining the pH of the contents of the stomach at a level of 3.5-5.0 for 15-30 minutes. Antacids are prescribed at least six times a day. When treating patients with gastritis or peptic ulcer, it is advisable to prescribe antacids 1-1.5 hours after a meal. With gastroesophageal reflux, diaphragmatic hernia, drugs are taken immediately after meals and at night. The duration of the use of antacids should not exceed 2 weeks (see below).

Absorbable antacids intensely bind hydrochloric acid, but their action is short-lived, the phenomenon of "acid rebound" is possible. They are rapidly absorbed from the intestine and, with frequent use, lead to the development of uncompensated metabolic alkalosis. The change in the acid-base state is also determined by the peculiarities of the interaction with the digestive juices: when sodium bicarbonate is prescribed * neutralization of hydrochloric acid occurs with the formation of sodium chloride, the excess of which, entering the systemic circulation, contributes to the development

alkalosis. Especially quickly alkalosis occurs in violation of the excretory function of the kidneys. Alkalosis results in hypokalemia. Excretion of sodium bicarbonate* leads to alkalinization of the urine, which may contribute to the development of phosphate nephrolithiasis. Sodium-containing drugs in patients with a tendency to heart or kidney failure may cause edema. Excess intake of antacids and dietary calcium can lead to a condition called "milk-alkaline syndrome", which is manifested by a combination of hypercalcemia and kidney failure with signs of alkalosis. IN acute form this syndrome develops within a week after treatment with soluble antacids and is manifested by a feeling of weakness, nausea, vomiting, headache, mental disorders, polyuria, an increase in serum calcium, creatinine. Currently, sodium bicarbonate has become less commonly used, mainly for the rapid relief of heartburn and abdominal pain.

The most serious side effects of aluminum-containing antacids can occur when they are taken for a long time or when high doses are used. The preparations of this group form insoluble aluminum phosphate in the small intestine, thus, the absorption of phosphates is disturbed. Hypophosphatemia is manifested by malaise, muscle weakness, with a significant deficiency of phosphates, osteomalacia and osteoporosis can occur. A small amount of aluminum still enters the blood, and with prolonged use, aluminum affects bone tissue, disrupting mineralization, toxic effect on osteoblasts, and disrupting the function of the parathyroid glands. Also, aluminum inhibits the synthesis of the active metabolite of vitamin D 3 - 1,25-dihydrooxycholecalciferol. In addition, a number of serious, even fatal, side effects can occur: damage to bone tissue and brain, nephropathy.

Calcium and aluminum preparations contribute to stool retention. Excess magnesium preparations can cause diarrhea. When prescribing calcium carbonate, 10% of it is absorbed, which sometimes leads to hypercalcemia. This, in turn, reduces the production of parathyroid hormone, delays the excretion of phosphorus, and there is a threat of tissue calcification, nephrolithiasis and renal failure.

The silicon in magnesium trisilicate can be excreted in the urine, which contributes to the formation of kidney stones.

Non-absorbable antacids are contraindicated in severe renal dysfunction, as well as in case of hypersensitivity to the components of the drug, pregnancy, breastfeeding(you can use phosphalugel *), Alzheimer's disease. With caution

In most cases, drugs should be used in the elderly and children (the use of some antacids is contraindicated in children under 10 years of age).

Interaction

By neutralizing hydrochloric acid, antacids accelerate the evacuation of gastric contents along with other drugs. The absorption rate of drugs of weak bases (chlorpromazine *, anaprilin *, trimethoprim) increases, as the pH of gastric juice increases. At the same time, the adsorption of sulfonamides, barbiturates (weak acids) slows down. With simultaneous intake, the absorption from the gastrointestinal tract of digoxin, indomethacin and other NSAIDs, salicylates, chlorpromazine, phenytoin, histamine H 2 receptor blockers, beta-blockers, isoniazid, tetracycline antibiotics, fluoroquinolones, azithromycin, rifampicin, ketoconazole, penicillamine, indirect anticoagulants, barbiturates, dipyridamole, bile acids (chenodeoxycholic and ursodeoxycholic), iron and lithium preparations, quinidine, mexiletine, preparations containing phosphorus. When taken simultaneously with drugs that have an enteric dosage form, a change in the pH of gastric juice (more alkaline reaction) can lead to accelerated destruction of the membrane and cause irritation of the mucous membrane of the stomach and duodenum. When used together, m-anticholinergics, slowing down gastric emptying, enhance and lengthen the action of non-absorbable antacids. Alkalinization of urine can lead to a change in the effectiveness of the antimicrobial action of antibiotics in the urinary tract.

M-anticholinergics

The m-cholinergic blockers used in diseases of the digestive system include the following groups of drugs:

Preparations of belladonna (belladonna): belladonna tincture, belladonna extract; active agents - hyoscyamine, scopolamine, etc.;

Combined belladonna preparations: becarbon *, bellastezin *, bellalgin *;

Preparations of natural and synthetic compounds with anticholinergic properties: atropine, platifillin, hyoscyamine, hyoscine butylbromide (buscopan *), metacin *, pirenzepine (gastrocepin *).

Mechanism of action and main pharmacodynamic effects

M-anticholinergics act on muscarinic receptors of organs and tissues in the region of the endings of parasympathetic nerve fibers. Blockade results:

Decreased secretion of digestive and bronchial glands;

Inhibition of the motor activity of the esophagus, stomach and intestines;

Decreased tone of the bronchi, bladder;

Improvement of atrioventricular conduction;

Tachycardia;

Pupil dilation;

Spasm of accommodation.

Against the background of taking anticholinergic drugs, the tone decreases and the strength of contractions decreases smooth muscle all hollow organs. They reduce the basal and nocturnal secretion of gastric juice, to a lesser extent, the secretion stimulated by food. By reducing the volume and general acidity of gastric juice, they reduce the amount of mucin, reduce the possibility of injury to the mucous membrane of the stomach and duodenum. Effects on motility and gastric secretion are not always parallel; the latter is blocked only when the influence of the cholinergic reaction in the regulation of the secretion of gastric juice prevails.

An overdose of m-anticholinergics is characterized by agitation, hallucinations, convulsions, respiratory paralysis. The pupil expands (mydriasis), due to paresis of the circular muscles of the iris and the ciliary body, paralysis of accommodation occurs, and intraocular pressure rises. In toxic doses, they block n-cholinergic receptors in the autonomic ganglia and skeletal muscles. Due to the inhibition of the vasomotor center and sympathetic ganglia, hypotension joins.

Atropine reduces the secretion of salivary glands, reduces the secretion of mucin and proteolytic enzymes by the glands of the stomach and small intestine. To a lesser extent, it inhibits the production of hydrochloric acid in the stomach.

Platifillin in its action is close to atropine, but its effectiveness is lower.

Chlorosil* in their own way pharmacological properties also similar to atropine, is a peripheral anticholinergic.

Metacin* considered a quaternary nitrogenous compound. Almost does not penetrate the blood-brain and blood-ophthalmic barriers, has a predominantly peripheral effect. To a lesser extent than atropine, it increases the heart rate.

Pirenzepine predominantly blocks intragastric acid production. Pirenzepine is a representative of a subgroup of specific blockers of m 1 -cholinergic receptors. It selectively inhibits the secretion of hydrochloric acid and pepsinogen and only slightly blocks

ruits m-cholinergic receptors of the salivary glands, heart, smooth muscles of the eye and other organs. According to the chemical structure, pirenzepine is similar to tricyclic antidepressants and has a greater affinity for m 1 -cholinergic receptors located in the nerve plexuses of the stomach, and not on the parietal cells themselves and in smooth muscles. That is why the effect of the drug is predominantly antisecretory, but not antispasmodic. Pirenzepine suppresses basal and stimulated production of pepsin, but does not affect the secretion of gastrin and a number of other gastrointestinal peptides (somatostatin, neurotensin, secretin). Pirenzepine has been shown to have cytoprotective properties. Pirenzepine reduces the basal secretion of the stomach by 50% when taken orally and by 80-90% when administered intravenously.

Indications and dosing regimen

Atropine-like drugs for the treatment of gastric and duodenal ulcers are rarely used due to a slight effect on acid production and a large number of systemic effects. They are used, for example, in severe pain syndrome, in the presence of pylorospasm.

Indications for the use of pirenzepine:

Treatment and prevention of peptic ulcer of the stomach and duodenum (as an aid);

Chronic gastritis with increased secretory function of the stomach, erosive esophagitis, reflux esophagitis, Zollinger-Ellison syndrome;

Erosive and ulcerative lesions of the gastrointestinal tract that occur during therapy with antirheumatic and anti-inflammatory drugs.

Pirenzepine is prescribed for adults inside in the first 2-3 days - 50 mg 3 times a day 30 minutes before meals, then 50 mg 2 times a day. The course of treatment is 4-6 weeks. If necessary, administered intramuscularly or intravenously, 5-10 mg 2-3 times a day. Combined oral and parenteral administration is possible. Maximum dose when taken orally - 200 mg / day.

Pharmacokinetics

After oral administration, pirenzepine is poorly absorbed from the gastrointestinal tract. Bioavailability is 20-30%, while taking with food - 10-20%. The maximum concentration of 50 pg / ml is reached after 2 hours. T 1 / 2 is 10-12 hours. The average elimination half-life is 11 hours. About 10% is excreted unchanged in the urine, the rest - with feces. A very small amount of pirenzepine is metabolized. Plasma protein binding - 10-12%.

Poorly penetrates through the BBB. Comparative pharmacokinetics of the main m-anticholinergics are given in table. 20-2.

Table 20-2. Pharmacokinetics of m-anticholinergics

When using m-anticholinergics, there is a feeling of dry mouth, mydriasis, tachycardia, disturbance of accommodation, impaired urination, atony of the stomach and intestines. When prescribing drugs in submaximal doses, the development of motor and mental disorders is possible. Contraindications to the appointment of m-cholinergic blockers: glaucoma, benign prostatic hyperplasia. Tolerability of pirenzepine is usually good, adverse reactions are mild and do not require discontinuation of the drug. The drug usually does not cause an increase in intraocular pressure, urinary disorders and adverse events from the cardiovascular system. However, patients with glaucoma, arrhythmias, prostate adenoma, pirenzepine is prescribed with caution. Absolute contraindications to the use of m-anticholinergics - prostatic hyperplasia, paralytic ileus, toxic megacolon, ulcerative colitis, pyloric stenosis, I trimester of pregnancy; hypersensitivity to pirenzepine. It is undesirable to use atropine-like drugs for cardia insufficiency, hernia of the esophageal opening of the diaphragm and reflux esophagitis, which occur as a concomitant pathology.

Interaction

With simultaneous use with anticholinergic agents, it is possible to increase anticholinergic effects. With simultaneous use with opioid analgesics, the risk of severe constipation or urinary retention increases.

With simultaneous use, it is possible to reduce the effect of metoclopramide on the motor activity of the gastrointestinal tract.

The simultaneous use of pirenzepine and H2-histamine receptor blockers leads to potentiation of their antisecretory effects. Pirenzepine reduces the stimulating effect of alcohol and caffeine on gastric secretion.

Blockers of H 2 -histamine receptors (H 2 -histamine blockers)

H2-histamine receptor blockers include cimetidine, ranitidine (zantac*, acilok*, ranisan*), famotidine (gastrosidin*, quamatel*, ulfamide*, famosan*), nizatidine, roxatidine.

Mechanism of action and main pharmacological effects

Common in the mechanism of action of these drugs is the competitive inhibition of the action of histamine on the H 2 -histamine receptors of the parietal cell membrane.

H 2 -histamine blockers - specific antagonists of H 2 -histamine receptors. In accordance with the laws of competitive antagonism of H 2 -histamine blockers inhibit the secretory reactions of parietal cells, depending on the dose. When they are taken, basal acid production, nocturnal secretion, secretion of hydrochloric acid stimulated by pentagastrin, H2-histamine receptor agonists, caffeine, insulin, false feeding, stretching of the fundus of the stomach are suppressed. In high doses, H 2 -histamine blockers suppress secretion almost completely. When taken repeatedly, the effect, as a rule, is reproduced and no pronounced tolerance is detected. At the same time, categories of patients with peptic ulcer with refractoriness to therapy with H2-histamine blockers were identified.

The course use of these drugs can lead to increased formation of prostaglandin E 2 in the mucous membrane of the stomach and duodenum, through which a cytoprotective effect is realized. When using H 2 -histamine blockers, pepsin production decreases by 30-90%, but the secretion of bicarbonate and mucus changes little. These drugs improve microcirculation in the mucous membrane. It has been proven that H 2 -histamine blockers inhibit the degranulation of mast cells, reduce the content of histamine in the periulcerous zone and increase the number of DNA-synthesizing epithelial cells, thereby stimulating reparative processes.

Classification

Among H 2 -histamine blockers, drugs are distinguished: I generation - cimetidine;

II generation - ranitidine;

III generation - famotidine;

IV generation - nizatidine;

V generation - roxatidine.

General principle the chemical structure of H 2 -histamine blockers is the same, however, specific compounds differ from histamine in a "weighted" aromatic part or in a change in aliphatic radicals. Cimetidine contains an imidazole heterocycle as the backbone of the molecule. Other substances are derivatives of furan (ranitidine), thiazole (famotidine, nizatidine) or more complex cyclic complexes (roxatidine).

The main differences between H 2 -blockers:

By selectivity of action, that is, by the ability to interact with histamine receptors of only type 2 and not affect type 1 receptors;

By activity, that is, by the degree of inhibition of acid production;

By lipophilicity, that is, by the ability to dissolve in fats and penetrate through cell membranes into tissues. This, in turn, determines the systemic action and the effect of drugs on other organs;

Tolerability and frequency of side effects;

By interaction with the cytochrome P-450 system, which determines the rate of metabolism of other drugs in the liver;

Withdrawal syndrome.

Cimetidine belongs to the I generation of blockers of H 2 -receptors of histamine of the parietal cells of the gastric mucosa. Suppresses the production of hydrochloric acid, both basal and stimulated by food, histamine, gastrin, and to a lesser extent acetylcholine. Reduces the activity of pepsin. Inhibits microsomal liver enzymes. The duration of the antisecretory effect of cimetidine is 6-8 hours. The concentration of gastrin in the blood serum does not change significantly. Along with a pronounced ability to inhibit gastric acid secretion, cimetidine causes inhibition of the motor activity of the stomach, a decrease in the rhythmic component of the motor activity, a decrease in the amplitude of the contraction of the antrum, and a slowdown in the passage of gastric contents. In the body, cimetidine binds not only to the H 2 -histamine receptors of the stomach, as it has additional binding sites to other tissue receptors, and in some patients these interactions can lead to clinically important side effects.

reactions. When used in high doses, cimetidine may affect H1 receptors.

Ranitidine, due to its unique structure, selectively binds to H2-histamine receptors in the stomach. Ranitidine has a longer antisecretory effect: it reduces both the volume of secreted gastric juice and the concentration of hydrogen ions in it. Ranitidine is 4-10 times more active than cimetidine. In patients with peptic ulcer, ranitidine significantly reduces daily intragastric acidity and, especially, nocturnal acid secretion, thereby relieves pain and promotes rapid healing of ulcers. When you stop taking ranitidine and cimetidine, you may develop a withdrawal syndrome.

Famotidine compared with ranitidine has a greater selectivity and duration of action, it is 40 times more active than cimetidine and 8-10 times more active than ranitidine, does not cause withdrawal syndrome. Practically does not interact with the cytochrome P-450 system, does not affect the metabolism of other drugs, does not reduce the activity of alcohol dehydrogenase in the liver. Famotidine does not have an antiandrogenic effect, does not cause impotence; does not increase the level of prolactin, does not cause gynecomastia. The frequency of side effects is not more than 0.8%.

Ranitidine, famotidine and subsequent generations of drugs have greater selectivity. Differences in the effectiveness of H 2 -histamine blockers are determined by the doses of drugs necessary for the development of an antisecretory effect. In addition, the strength of binding to receptors determines the duration of action. A drug that binds strongly to the receptor dissociates slowly, therefore, has a longer blockade of acid formation. Studies have shown that an effective decrease in basal secretion is maintained after taking cimetidine for 2-5 hours, ranitidine - 7-8 hours, famotidine - 10-12 hours. All H 2 -blockers are hydrophilic drugs. Cimetidine is the least hydrophilic and moderately lipophilic drug, therefore it is able to penetrate into different organs and tissues, acting on the H2-histamine receptors localized in them. This determines the presence maximum number side effects among drugs of this pharmacological group. Ranitidine and famotidine are highly hydrophilic, poorly penetrate into tissues, and have a predominant effect on H 2 -histamine receptors of parietal cells.

Nizatidine and roxatidine have not yet been widely used in clinical practice, and the advantages of their use compared to previous generations of drugs have not been studied enough.

Pharmacokinetics

The main pharmacokinetic parameters of H 2 -histamine receptor blockers are presented in table. 20-3.

Table 20-3. Pharmacokinetic parameters of H 2 -histamine blockers

When taken orally, H 2 -histamine blockers have a relatively high bioavailability, the value of which in some of them reaches 90%. The greatest bioavailability is observed in cimetidine, the smallest - in famotidine. Communication with blood proteins of these drugs does not exceed 26%. It should be noted that with course monotherapy, the residual concentration of cimetidine in the morning, after evening administration, is practically not determined, and for ranitidine it is 300 ng / ml.

H 2 -histamine blockers undergo partial biotransformation in the liver. In a significant amount (50-60%), especially when administered intravenously, they are excreted unchanged by the kidneys. The half-life ranges from 1.9 to 3.7 hours. Taking cimetidine after a meal changes its pharmacokinetics, leading to the formation of a double-humped concentration-time curve (changes in portal blood flow, filling of mucosal receptors with food ingredients, and avoidance of the absorption-excretory structures of the hepatocyte ).

Thus, H 2 -histamine blockers are characterized by mixed (renal and hepatic) clearance. In patients with kidney failure and in case of impaired liver function, as well as in the elderly, the clearance of H 2 -histamine blockers is reduced. The drug enters the primary urine not only with the filtrate, but also due to the mechanism of active tubular secretion. H 2 -histamine blockers are able to penetrate the blood-brain barrier.

It should be borne in mind that with long-term administration of drugs of this group, a high activity of histidine decarboxylase is constantly maintained, which leads to the accumulation of histamine in the mucous membrane and an increase in reparative processes at the beginning of treatment. This causes the trophic positive effects of histamine. With the accumulation of an excessive amount of histamine, dystrophic processes begin to develop with the formation of erosions. In the case of rapid cancellation of H 2 -histamine blockers, withdrawal syndrome ("rebound") often develops.

In lactating women, H 2 -histamine blockers can be found in breast milk in quantities sufficient for the pharmacological effects on the child.

Cimetidine blocks microsomal oxidation by inhibiting the activity of cytochrome P-450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, which can lead to impaired biotransformation of endogenous and exogenous substances metabolized by microsomal oxidation. Ranitidine and representatives of subsequent generations of H 2 -histamine blockers have less effect on cytochrome P-450 isoenzymes, but it is known that ranitidine is an inhibitor of CYP2D6, CYP3A4. Famotidine and representatives of subsequent generations of H 2 -histamine blockers have practically no effect on the cytochrome P-450 system.

Indications for use and dosing regimen

H 2 -histamine blockers are used in such acid-dependent diseases as chronic gastritis, duodenitis, peptic ulcer of the stomach and duodenum, Zollinger-Ellison syndrome, symptomatic ulcers that developed against the background of extensive burns, concomitant injuries, sepsis, cerebrovascular accident, renal failure and etc. H 2 -Histamine blockers are indicated for steroid ulcers of the stomach and duodenum, reflux esophagitis, anastomositis.

In peptic ulcer disease, all H2-histamine blockers in appropriate doses are therapeutically equivalent, they provide the disappearance of pain in most patients within 1-10 days, and endoscopically confirmed healing is observed after 4 weeks in 60-80% and after 6 weeks in 80-92% cases, which is considered adequate for this disease. With large ulcers against the background of the use of aspirin or other non-steroidal anti-inflammatory drugs, as well as in smoking patients, the treatment process is lengthened. Prophylactically, H 2 -histamine blockers are used 1-2 times a day in the spring and autumn period in medium therapeutic doses.

H 2 -histamine blockers are used to prevent Mendelssohn's syndrome. Mendelssohn's syndrome (acid-aspiration syndrome) is a hyperergic reaction to aspiration of acidic gastric contents into the respiratory tract due to vomiting or passive displacement of the contents of the stomach into the oropharynx in the patient's coma, anesthesia, with oppression of larynx-pharyngeal reflexes of any etiology.

Cimetidine for the treatment of exacerbations of duodenal ulcer is prescribed 200-400 mg 3 times a day (during meals) and 400-800 mg at night. It is possible to prescribe at a dose of 800 mg in 1 dose (at bedtime), as well as 400 mg 2 times a day. The maximum daily dose is 2.0 g. The duration of the course of treatment is 4-6 weeks. For the prevention of exacerbations, 400 mg per night are prescribed. The average duration of treatment for an ulcer associated with reception NSAIDs - 8 weeks. Doses are the same. With reflux esophagitis, 400 mg are prescribed 4 times a day with meals and at night. The course of treatment is 4-8 weeks. With Zollinger-Ellison syndrome - 400 mg 4 times a day, if necessary, the dose can be increased. In order to prevent bleeding and in the treatment of erosive and ulcerative lesions of the upper gastrointestinal tract caused by stress, cimetidine is prescribed parenterally, when the patient's condition stabilizes, they switch to oral administration in daily dose up to 2.4 g (200-400 mg every 4-6 hours). In preparation for surgery, 400 mg is prescribed 90-120 minutes before the start of general anesthesia. In case of impaired renal function, the dose of cimetidine should be reduced. With a creatinine clearance of 30-50 ml / min - up to 800 mg / day, 15-30 ml / min - up to 600 mg / day, less than 15 ml / min - up to 400 mg / day.

The recommended dose of ranitidine for exacerbation of duodenal ulcers or benign gastric ulcers is 300 mg (divided into two doses of 150 mg in the morning and evening or taken once a day). Treatment is continued until ulcer scarring or, if re-examination is not possible, for 4-8 weeks. In most cases, duodenal and gastric ulcers heal after 4 weeks. In some cases, it may be necessary to continue treatment for up to 8 weeks. In the treatment of peptic ulcer, abrupt discontinuation of the drug is not recommended (especially before scarring of the ulcer), it is usually recommended to switch to a maintenance dose of 150 mg at night. In the treatment of non-ulcer dyspepsia and gastritis, a shorter course is possible. In many countries, ranitidine 75 mg is sold as an over-the-counter drug for use in non-ulcer dyspepsia at 75 mg 4 times a day. With reflux esophagitis, the recommended dose is 150 mg 2 times a day for 8 weeks, with

up to 150 mg 4 times a day. In addition, the improvement of the condition contributes to raising the head end of the bed and treatment with metoclopramide. For the prevention of recurrence of peptic ulcer, it is recommended to take 150 mg once a day, before going to bed. In conditions with pathological hypersecretion, for example, Zollinger-Ellison syndrome, the recommended dose of ranitidine is 600-900 mg per day in divided doses. In severe cases, doses up to 6 g per day were used, which were well tolerated by patients. Recommended for Helicobacter pylori regimens using ranitidine - see the section on proton pump inhibitors. The usual dose for the prevention of recurrent gastrointestinal bleeding in patients with peptic ulcer is 150 mg twice daily. Surgical patients with a risk of aspiration of gastric contents are prescribed 300 mg of ranitidine orally on the evening before surgery.

Famotidine for peptic ulcer of the stomach and duodenum in the acute stage is prescribed 20 mg 2 times a day (morning and evening) or 40 mg 1 time per day at night. If necessary, the daily dose can be increased to 80-160 mg. The course of treatment is 4-8 weeks. In order to prevent relapses - 20 mg 1 time per day at bedtime. With reflux esophagitis - 20-40 mg 2 times a day for 6-12 weeks. In Zollinger-Ellison syndrome, the dose of the drug and the duration of the course of treatment are set individually, the initial dose is usually 20 mg every 6 hours. In case of general anesthesia, to prevent aspiration of gastric juice, 40 mg orally on the evening before the operation and / or in the morning before the operation, i.v. or drip (used when it is impossible to ingest). The usual dose is 20 mg 2 times a day (every 12 hours). In the presence of Zollinger-Ellison syndrome, the initial dose is 20 mg every 6 hours. In the future, the dose depends on the level of secretion of hydrochloric acid and clinical condition sick. In renal failure, if creatinine clearance is<30 мл/мин или креатинин сыворотки крови >3 mg / 100 ml, the daily dose of the drug should be reduced to 20 mg or the interval between doses should be increased to 36-48 hours.

Side effects and contraindications

The ratio of toxic and therapeutic doses for all H2-histamine blockers is very high. Different drugs in this group cause side effects with different frequency. When using cimetidine, it is 3.2%, ranitidine - 2.7%, famotidine - 1.3%. There may be a headache, a feeling of fatigue, drowsiness, anxiety, nausea, vomiting, abdominal pain, flatulence, violations of the act of de-

feces, myalgia, allergic reactions. Acute pancreatitis, hepatocellular, cholestatic or mixed hepatitis with or without jaundice, bone marrow hypoplasia, severe CNS damage (resulting from penetration of drugs through the blood-brain barrier), including confusion, reversible visual acuity disturbances, dizziness, agitation, hallucinations, hyperkinesis, depression, were noted, although extremely rarely, but with the use of all antagonists of H 2 -histamine receptors.

Neurotropic adverse reactions are more likely to occur in the elderly and in violation of the function of the liver and kidneys, as well as in violation of the integrity of the blood-brain barrier. Changes in the blood (thrombocytopenia, leukopenia, neutropenia, aplastic and immune hemolytic anemia) and a moderate reversible increase in liver enzymes, serum creatinine levels are described. The prevalence of these reactions is low.

H 2 -histamine blockers can cause reversible, associated with idiosyncrasy, hematological side effects. They usually occur within the first 30 days of treatment, are reversible, and most commonly present with thrombocytopenia and granulocytopenia. Cases of alopecia, increased blood creatinine, bradycardia and hypotension, intestinal obstruction, mental disorders, lesions of the neuromuscular apparatus, paresthesias are described. Similar reactions against the background of the use of ranitidine, famotidine occur mainly with the use of high doses of drugs, for example, with Zollinger-Ellison syndrome.

Violations of the endocrine system are due to the ability of H 2 -histamine blockers to displace endogenous testosterone from the connection with receptors, as well as drugs containing this hormone, leading to sexual disorders (impotence, gynecomastia). Famotidine causes these effects less frequently than cimetidine and ranitidine. They (effects) are dose-dependent, occur against the background of long-term use of drugs, are reversible (disappear when the drug is discontinued or replaced with another one).

Famotidine has a side effect mainly on the gastrointestinal tract: either diarrhea or (less often) constipation develops. Diarrhea is the result of antisecretory action. A decrease in hydrochloric acid production increases the pH in the stomach, which prevents the conversion of pepsinogen to pepsin, which is involved in the breakdown of food proteins. In addition, a decrease in the production of gastric juice, as well as blockade of H 2 -histamine receptors in the pancreas, cause a decrease in the release of digestive enzymes.

pancreas and bile. All this leads to a violation of the digestive process and the development of diarrhea. However, the frequency of these complications is low (for famotidine - 0.03-0.40%) and usually does not require discontinuation of treatment. Similar effects are characteristic of all H 2 -histamine blockers. They are dose-dependent and can be attenuated by lowering the dose of the drug.

H 2 -blockers can disrupt the function of the cardiovascular system by blocking H 2 -histamine receptors in the myocardium, the vascular wall. In those suffering from cardiovascular diseases and elderly patients, they can cause arrhythmias, increase heart failure, and provoke coronary spasm. Hypotension is sometimes observed with intravenous administration of cimetidine.

Hepatotoxicity of H 2 -histamine blockers, manifested by hypertransaminasemia, hepatitis, impaired activity of cytochrome P-450, is associated with the metabolism of these drugs in the liver. This is most characteristic of cimetidine. H 2 -histamine blockers are prescribed to patients with impaired liver function with caution and in reduced doses.

When using famotidine, due to its insignificant metabolism, the frequency of such complications is minimal.

H 2 -histamine blockers can worsen the course of broncho-obstructive diseases, leading to bronchospasm (action on H 1 -histamine receptors). A side effect characteristic of H 2 -histamine blockers (mainly cimetidine and ranitidine) is the development of a withdrawal syndrome. That is why it is recommended to reduce the dose gradually.

Contraindications to the appointment of H 2 -histamine blockers: pregnancy, lactation, childhood(up to 14 years), severe violations of the liver and kidneys, disorders heart rate. Drugs should be taken with caution in the elderly.

Interaction

When prescribing with other drugs, it should be borne in mind that cimetidine and, much less often, ranitidine inhibit the activity of cytochrome P-450 isoenzymes CYP1A2, CYP2C9, CYP2D6, CYP3A4, which can lead to an increase in plasma concentrations of co-administered drug substrates of these isoenzymes, for example, theophylline, erythromycin, ethmozine*, indirect anticoagulants, phenytoin, carbamazepine, metronidazole. Cimetidine can also inhibit the metabolism of tricyclic antidepressants, benzodiazepines, β-blockers, calcium channel blockers, amiodarone, lidocaine. With simultaneous use with quinidine concentration

the concentration of quinidine in the blood plasma increases, there is a risk of increased side effects; with quinine - it is possible to reduce the excretion of quinine and increase its T 1 / 2, there is a risk of increased side effects.

Ranitidine also binds to the enzymes of the system, but with a lower affinity, so its effect on drug metabolism is negligible. Famotidine, nizatidine, roxatidine generally do not have the ability to bind to the cytochrome system and inhibit the metabolism of other drugs.

Due to the possible decrease in the rate of hepatic blood flow by 15-40%, especially with intravenous use of cimetidine and ranitidine, the first pass metabolism of drugs with high clearance may decrease. Famotidine does not change the rate of portal blood flow.

By analogy with antacids, H 2 -histamine receptor antagonists, by increasing the pH in the stomach, can affect the bioavailability of some drugs. It has been established that standard doses of cimetidine and ranitidine increase the absorption of nifedipine, enhancing its antihypertensive effect. Ranitidine also reduces the absorption of itraconazole and ketoconazole.

With simultaneous use with digoxin, both an increase and a decrease in the concentration of digoxin in the blood plasma are possible. With simultaneous use with carvedilol, the AUC of carvedilol increases without changing its Cmax in blood plasma. With simultaneous use with loratadine, the concentration of loratadine in the blood plasma increases, no increase in side effects was noted. Smoking reduces the effectiveness of ranitidine.

Cimetidine reduces the inactivation of pancreatic enzymes in the intestine. On the contrary, the simultaneous use of H 2 -histamine blockers reduces the bioavailability of itraconazole and ketoconazole.

Antacids, sucralfate slow down the absorption of ranitidine, famotidine, and therefore, with simultaneous use, the interval between taking antacids and ranitidine should be at least 1-2 hours.

Drugs that inhibit hematopoiesis in the bone marrow, while using famotidine, increase the risk of developing neutropenia.

H 2 -histamine blockers are weak bases, excreted by active secretion in the tubules of the kidneys. Interactions may occur with other drugs that are excreted by the same mechanisms. So, cimetidine and ranitidine reduce the renal excretion of zidovudine, quinidine, novocaine-

Yes*. Famotidine does not alter the excretion of these drugs, possibly due to the use of other transport systems. In addition, the average therapeutic doses of famotidine provide low plasma concentrations that cannot significantly compete with other drugs at the level of tubular secretion.

Pharmacodynamic interactions of H 2 -histamine blockers with other antisecretory drugs (for example, anticholinergics) may enhance therapeutic efficacy. The combination of H 2 -histamine blockers with drugs that act on Helicobacter (bismuth drugs, metronidazole, tetracycline, amoxicillin, clarithromycin) accelerates the healing of peptic ulcers.

With simultaneous use with fentanyl, it is possible to enhance the effects of fentanyl; with flecainide - the concentration of flecainide in the blood plasma increases due to a decrease in its renal clearance and metabolism in the liver under the influence of cimetidine.

Unfavorable pharmacodynamic interactions have been observed with preparations containing testosterone. Cimetidine displaces the hormone from its association with receptors and increases its plasma concentration by 20%. Ranitidine and famotidine do not have this effect.

When taken with fluvastatin, fluvastatin absorption may increase; with fluorouracil - the concentration of fluorouracil in the blood plasma increases by 75%, the side effects of fluorouracil increase; with chloramphenicol - cases of severe aplastic anemia have been described; with chlorpromazine - both a decrease and an increase in the concentration of chlorpromazine in the blood plasma. With simultaneous use with cyclosporine, an increase in the concentration of cyclosporine in the blood plasma cannot be excluded. With simultaneous use, the concentration in the blood plasma of pefloxacin increases (when taken orally).

With simultaneous use with oral hypoglycemic agents, sulfonylurea derivatives, hypoglycemia was observed in rare cases.

Proton pump inhibitors

Mechanism of action and main pharmacodynamic effects

H+/K+-ATPase inhibitors are benzimidazole derivatives. Drugs in an alkaline neutral medium are pharmacologically inactive (prodrugs), they are lipophilic weak bases, poorly soluble in water. In an acidic environment, they are unstable, so

mu commercial dosage forms are enteric tablets or granules in gelatin capsules (the higher the pH of the medium, the greater the percentage of release of the substance from the granules or tablets). The drugs are absorbed in the small intestine. Being weak bases, proton pump inhibitors easily penetrate from plasma into the acidic environment of the secretory tubule, where they form sulfonic acid and cationic sulfenamide of a tetracyclic structure, which covalently interacts with SH groups on the extracellular, luminal domain of H + /K + -ATPase. When two inhibitor molecules bind to one enzyme molecule, an almost irreversible block is formed, since the cationic sulfenamide poorly dissociates from the receptor (Table 20-4). The restoration of the activity of the molecular pump is mainly due to its synthesis de novo.

Table 20-4. Antisecretory effect of proton pump inhibitors after 5 days of treatment (according to Scholtz H.E. et al., 1995)

Since proton pump inhibitors are converted into pharmacologically active substances only at low pH values ​​found in the secretory tubules of parietal cells, this is believed to be the reason for their high selectivity and safety. However, it is possible to activate drugs in moderately acidic tissues with inhibition of renal Na + / K + -ATPase and the formation of reactive oxygen species by neutrophils, inhibition of T-killers and chemotaxis of polymorphonuclear cells.

H + /K + -ATPase blockers potentiate the synthesis of mucus and bicarbonates in the antrum of the stomach and in the duodenum.

Classification

The classification of proton pump inhibitors is very conditional. With the development of a new group of drugs - benzimidazole derivatives, due to the common mechanism of their action, the classification was based on the order of their creation (generation of proton pump inhibitors). However, the direction of the search for new highly efficient pre-

paraty of this pharmacological group went in two directions: on the one hand, rabeprazole was created, which differs in chemical structure from representatives of previous generations; on the other hand, esomeprazole was created, which is a monoisomer (S-isomer) of omeprazole, a representative of the first generation of proton pump inhibitors. The synthesis of esomeprazole is based on the separation of the racemic mixture of omeprazole into right- and left-handed (respectively R- and S-) isomers. The method of this separation was recognized as a fundamental achievement, its developers were awarded the Nobel Prize in Chemistry in 2001. The R-form of omeprazole is less effective than the S-form (esomeprazole) due to their differences in biochemical availability. Most of the R-form is metabolized in the liver and does not reach the parietal cell. These advantages in the metabolism of esomeprazole result in an increase in AUC compared to that of omeprazole.

Rabeprazole and esomeprazole showed a longer, compared with previous generations of H + /K + -ATPase blockers, the duration of the main pharmacodynamic effect (blockade of acid production), on the other hand, two directions in the development of the pharmacological group introduce disagreement into the principles of constructing a classification by generations (Fig. 20 -one).

Rice. 20-1. Directions for the development of the pharmacological group of drugs - proton pump inhibitors (scheme).

Pharmacokinetics

The pharmacokinetics of proton pump inhibitors depends on the dose used. This is due to their property, such as high lability in an acidic environment. They are able to block intragastric acid production, increase their own bioavailability (more typical for omeprazole, esomeprazole and lansoprazole; the bioavailability of pantoprazole and rabeprazole practically does not change with prolonged use). Since proton pump blockers are unstable in an acidic environment, commercial dosage forms are available as enteric granules enclosed in gelatin capsules or enteric tablets. Comparative pharmacokinetics of proton pump inhibitors are shown in Table. 20-5.

It should be noted that the bioavailability of proton pump inhibitors changes in the presence of certain diseases of the liver, esophagus, stomach, intestines (for example, with reflux esophagitis, exacerbation of duodenal ulcer).

For patients with kidney disease or for the elderly, a reduction in the dose of proton pump inhibitors is not required. Despite a decrease in the clearance of proton pump inhibitors in the liver, there is no need to adjust the dose of the drug for patients with impaired function of this organ. Dose adjustment is not necessary for patients with varying degrees of renal insufficiency, as well as for patients with cirrhosis of the liver, despite a decrease in the total clearance of the inhibitor.

Omeprazole metabolites identified in plasma and urine samples are omeprazole sulfone, omeprazole sulfide, hydroxyomeprazole. Omeprazole is metabolized almost completely to an inactive sulfone and 100 times less active hydroxy derivative.

An interesting fact is that proton pump inhibitors are characterized by the effect of functional cumulation, that is, the accumulation of the antisecretory effect, and not the drug, occurs. Thus, with a sufficiently low half-life, given that the active form of the drug permanently blocks the functional activity of H + /K + -ATPase and the secretion of hydrochloric acid is restored only when new proton pump molecules appear, the duration of the main pharmacodynamic effect far exceeds the time spent by the drug in the blood .

Indications for use and dosing regimen Indications for use:

non-ulcer dyspepsia;

Peptic ulcer of the stomach and duodenum;

table 20-5. Main pharmacokinetic parameters of proton pump inhibitors

peptic ulcer;

stress ulcers;

Erosive and ulcerative esophagitis;

Reflux esophagitis;

Zollinger-Ellison syndrome;

Polyendocrine adenomatosis;

Systemic mastoidosis;

Infection Helicobacter pylori.

In gastric ulcer, duodenal ulcer and reflux esophagitis, omeprazole is prescribed 20 mg 1 time per day, lansoprazole 30 mg 1 time per day, pantoprazole 40 mg per day, rabeprazole 40 mg per day, esomeprazole 40 mg per day . If necessary (maintaining symptoms of dyspepsia or prolonging the healing of mucosal defects), increase the dose or duration of treatment (if necessary, up to 40 mg). With a duodenal ulcer, the course of treatment is 2-4 weeks, with a stomach ulcer and reflux esophagitis - 4-8 weeks. The drugs are used to prevent seasonal exacerbations or in the "on demand" mode, when the patient takes drugs on his own when short-term and mild dyspepsia occurs. With Zollinger-Ellison syndrome, the initial doses of drugs are increased (under the control of gastric secretion). With peptic ulcer, in the pathogenesis of which the bacterium Helicobacter pylori plays one of the leading roles, take double doses of proton pump inhibitors in combination with antibacterial drugs (Table 20-6).

Side effects and contraindications to the appointment

Frequent complaints of patients receiving proton pump inhibitors for a long time are headache, dizziness, dry mouth, nausea, diarrhea, constipation, general weakness, allergic reactions, various options skin rash, rarely - impotence, gynecomastia. With prolonged continuous use of proton pump inhibitors, a decrease in the production of protective hexosamine-containing gastric mucin is possible.

As a result of achlorhydria, colonization by microorganisms of the previously practically sterile mucous membrane of the stomach and duodenum can occur; hypergastrinemia, ECL cell hyperplasia, possibly increasing the risk of developing ECL cell carcinoma. It is possible to activate the drug in moderately acidic tissues with inhibition of the renal Na + / K + -ATPase and the formation of reactive oxygen species by neutrophils, inhibition of T-killers and chemo-

Table 20-6. Infection eradication therapy regimens Helicobacter pylori

taxis of polymorphonuclear cells, neutropenia, agranulocytosis. With prolonged use of omeprazole appear hyponatremia, vitamin B12 deficiency. Rarely candidiasis (as a consequence of immunodeficiency), autoimmune disorders. Cases of hemolysis, acute hepatitis, acute interstitial nephritis, acute renal failure are described. The problem of the possible effect of the drug on the fetus remains insufficiently studied.

Interaction

Omeprazole slows down the elimination of drugs metabolized in the liver by microsomal oxidation by cytochrome P-450 isoenzymes CYP2C9, CYP3A4, diazepam, phenytoin,

indirect anticoagulants. Omeprazole reduces the clearance of theophylline by 10%. Proton pump inhibitors change the pH-dependent absorption of drugs belonging to the groups of weak acids (retardation) and bases (acceleration). Sucralfate reduces the bioavailability of omeprazole by 30%, and therefore it is necessary to observe the interval between taking these drugs at 30-40 minutes. Antacids slow down and reduce the absorption of proton pump inhibitors, so they should be given 1 hour before or 1-2 hours after taking lansoprazole.

20.2. GASTROPROTECTORS

Gastroprotectors include drugs that increase the resistance of the mucous membrane of the stomach and duodenum to the effects of aggressive factors. Such gastroprotection can be carried out either by activating the natural mechanisms of protection of the mucous membrane, or by forming an additional protective barrier in the area of ​​erosion or ulcers.

The following pharmacological mechanisms of mucosal protection are known:

Stimulation of the resistance of cells of the gastroduodenal zone to adverse effects (true cytoprotection);

Increased secretion of mucus and a change in its qualitative characteristics towards greater resistance to acid-peptic aggression;

Stimulation of secretion by cells of the mucous membrane of bicarbonates;

Increasing the resistance of the capillary bed to aggression and normalization of microcirculation in the mucous membrane of the stomach and duodenum;

Stimulation of mucosal cell regeneration;

Mechanical protection of mucosal defects.

Mechanism of action and main pharmacodynamic effects

Classification

There are five groups of gastroprotectors:

Film-forming agents: sucralfate, preparations of colloidal bismuth (bismuth subnitrate and bismuth subsalicytate): de-nol*, tribimol*, ventrisol*;

Adsorbent and enveloping drugs: simaldrate (gelusil *, gelusil varnish *);

Cytoprotective: prostaglandins - a synthetic analogue of prostaglandin E-misoprostol;

Regeneration stimulants (reparants): methyluracil *, pentoxyl *, etadene *, methandienone (methandrostenolone *), nandrolone (retabolil *), potassium orotate, ATP preparations, biogenic stimulants (aloe tree leaves, kalanchoe juice * , apilac * , propolis), sea buckthorn oil, rosehip oil, elecampane root preparations, solcoseryl * , gastrofarm *, etc .;

Mucus stimulants: preparations of licorice root naked, carbenoxolone, dry cabbage juice *, etc.

Preparations of colloidal bismuth. In the acidic environment of gastric contents, they form a glycoprotein-bismuth complex, concentrated in the area of ​​erosive and ulcerative lesions. This creates a protective barrier that prevents the back diffusion of hydrogen ions, which accelerates the healing of erosion or ulcers. Bismuth preparations have little effect on aggressive factors of ulcer formation, but are able to prevent damage to the gastric mucosa by chemical irritants - ethanol, acetic acid, etc. It is known that under the influence of colloidal bismuth preparations, local synthesis of prostaglandin E 2 in the mucous membrane of the stomach or duodenum is increased by 50%. . Important in antiulcer therapy is the inhibitory effect of bismuth against Helicobacter pylori.

Sucralfate- complex sulfated disaccharide containing aluminum. The drug is similar to heparin, but lacks anticoagulant properties and consists of sucrose octasulfate. In the acidic environment of the stomach, it polymerizes, aluminum hydroxide is consumed when reacting with acid. The resulting polyanion forms strong bonds with positively charged radicals of the proteins of the gastric and duodenal mucosa, especially in the area of ​​erosions and ulcers, where the concentration of the drug is 5-7 times higher than in areas of healthy mucosa. This protective layer is relatively stable - it remains in the stomach up to 8 hours, in the duodenum up to 4 hours.

Sucralfate does not have pronounced antacid properties, but inhibits the peptic activity of gastric juice by approximately 30%. It is able to adsorb bile acids, pepsin and increase the synthesis of prostaglandins.

Prostaglandins are unsaturated carboxylic acids of endogenous origin and contain 20 carbon atoms in the form of a cyclopentane ring. Prostaglandins are derivatives of essential fatty acids that are part of the cell

membranes. Their precursor is arachidonic acid released from membranes under the influence of phospholipase A 2 . Many prostaglandins (G, A, I 2) inhibit gastric secretion, reducing the acidity and peptic activity of gastric juice; reduce vascular permeability, normalize microcirculation, enhance the secretion of mucus and bicarbonates. The gastroprotective properties of prostaglandins are associated with their ability to prevent mucosal necrosis when exposed to NSAIDs, ethanol, hypertonic saline, etc.

The effect of exposure to prostaglandins develops very quickly, within one minute when administered orally, and lasts up to two hours. Synthetic analogues of prostaglandins (misoprostol) are more stable in the body. Misoprostol (a synthetic analogue of prostaglandin E 1) binds to prostaglandin receptors on parietal cells, inhibiting basal, stimulated and nocturnal secretion. The action of the drug begins 30 minutes after ingestion and lasts at least 3 hours. It has been shown that at a dose of 50 μg the effect is short; at a dose of 200 mcg - more pronounced and prolonged.

Regeneration stimulants (reparants). Methyluracil * - an analogue of pyrimidine bases, stimulates protein synthesis in peptic ulcer disease, accelerates cell regeneration, promotes healing of ulcers, burns.

Methandienone (methandrostenolone *), nandrolone (retabolil *) - anabolic hormones. Stimulate the nitrogen balance, reduce the release of urea, potassium, sulfur, phosphorus. In patients, appetite increases, body weight increases, the period of convalescence after an exacerbation of a number of diseases is facilitated, the healing of ulcers, wounds, and burns is accelerated. These drugs are indicated for the treatment of emaciated peptic ulcer patients.

Biogenic stimulant solcoseryl* - non-protein extract of calf blood, accelerates tissue regeneration in case of ulcerative lesions, burns, frostbite, bedsores, etc.

Biogenic stimulants also include the aforementioned aloe arborescens, kalanchoe juice*, apilac*, propolis. Reparants with a complex mechanism of action on the healing of ulcers, burns, wounds - sea buckthorn oil, rosehip oil. They contain large amounts of carotenes, carotenoids, vitamins C, E, folic acid, etc. Under the action of sea buckthorn oil in the homogenate of the gastric mucosa, the content of acetylneuraminic acid increases, and the level of peroxides decreases. The roots of elecampane contain essential oil, the crystalline part of which (gelenin) consists of

mixtures of alantolactone lactones, its iso- and dihydroanalogues, and allantonic acid. The preparation of elecampane roots - alanton *, stimulates the processes of tissue regeneration, including ulcerative surfaces.

Due to low efficiency, the use of these drugs is currently limited.

Mucus stimulants. Licorice root is rich in biologically active substances. These include licuraside, glycyrrhizic acid (a triterpene glycoside * with anti-inflammatory properties), flavone glycosides, liquiritone *, liquiritoside (having an antispasmodic effect), essential oil, mucous and many other products of plant metabolism. In the early 60s, based on glycyrrhizic acid, a pentacyclic triterpene was synthesized, which, under the name carbenoxolone (biogastron, duogastron), was used in the treatment of patients with peptic ulcer. The drug in the course of use improved the quantity and quality of the mucous layer, which increased its resistance to acid-aggressive effects.

Pharmacokinetics

The pharmacokinetics of the main drugs of the group is given below.

Bismuth preparations have low bioavailability. With course treatment, the concentration of bismuth in the blood plasma reaches 50 μg / l after approximately one month. At the same time, the concentration of the drug in gastric juice remains at the level of 100 mg / l. The absorbed bismuth is concentrated in the kidneys and excreted in the urine. The unabsorbed part of bismuth is excreted in the feces in the form of sulfide. The half-life is 4-5 days. Occasionally, headaches, dizziness, diarrhea are noted. Bismuth encephalopathies have been described when the plasma concentration of the drug reached 100 μg / l.

Sucralfate is poorly absorbed from the gastrointestinal tract. Absorption is 3-5% of the administered dose (up to 5% of the disaccharide component and less than 0.02% of aluminum). It is excreted through the intestines - 90% unchanged, a small amount of sulfate disaccharide that enters the bloodstream is excreted by the kidneys. When administered orally, misoparostol is rapidly and completely absorbed (food delays absorption). With max comes in 12 minutes; 90% of the drug in plasma is protein bound. T 1 / 2 is 20-40 minutes. In the walls of the gastrointestinal tract and liver, it is metabolized to the pharmacologically active misoprostolic acid. 80% of metabolites are excreted in the urine, 15% - in the bile. C ss - after 2 days. It does not accumulate with repeated administration. It is excreted by the kidneys (80%) and with bile (15%). In case of impaired renal function, C max increases almost 2 times, T 1 / 2 lengthens.

Indications for use and dosing regimens

The described group of drugs is used in the treatment and prevention of patients with erosions and ulcers of the stomach and duodenum, with reflux esophagitis, gastritis. Bismuth preparations are part of the schemes for eradication Helicobacter pylori. Sucralfate is also indicated for hyperphosphatemia in patients with uremia who are on hemodialysis. Their therapeutic significance in peptic ulcer disease has decreased (due to the widespread use of anti-acid agents), however, each of the drugs has its own therapeutic "niche" and certain indications for use. Misoprostol is also used to prevent and treat non-steroidal gastropathy in patients with an increased risk of ulceration.

De-nol * is used 2 tablets (each 120 mg) a day half an hour before breakfast and lunch for 4-8 weeks. Bismuth preparations are most often used as part of anti-helicobather therapy regimens (see the table in the section on proton pump inhibitors).

Sucralfate is used orally 1 g 4 times a day or 2 g 2 times a day 1 hour before meals and at bedtime, the maximum daily dose is 8 g. The average duration of the treatment of peptic ulcer is 4-6 weeks, if necessary, up to 12 weeks In patients with hyperphosphatemia, with a decrease in the concentration of phosphates in the blood plasma, the dose of sucralfate may be reduced.

Misoprostol is prescribed for adults at 200 mcg 4 times a day (during or after meals and at night). Perhaps the use of 400 mcg 2 times a day (the last dose at night). In patients taking NSAIDs, misoprostol is used throughout the duration of NSAID treatment. The course of treatment for exacerbation of duodenal ulcer 4 weeks. If, according to endoscopy, complete scarring of the ulcer is not noted, treatment is continued for another 4 weeks.

Contraindications

Gastroprotectors are contraindicated in pregnancy, severe renal dysfunction, hypersensitivity to drugs. Misoprostol, which has a teratogenic effect, is contraindicated in pregnancy, lactation, as well as in violation of liver function, hypersensitivity to prostaglandins. De-nol * is not used in case of impaired renal function. Sucralfate is not prescribed for children under 4 years of age, patients with severe renal dysfunction, bleeding from the gastrointestinal tract, hypersensitivity to the drug, dysphagia or gastrointestinal obstruction.

Side effects

When using all gastroprotectors, headache, nausea, vomiting, violation of the act of defecation may occur. Occasionally, allergic reactions in the form of skin rash and itching are noted. When using misoprastol, diarrhea is often observed, menorrhagia, metrorrhagia are possible. Long-term use of large doses of bismuth preparations is not recommended, since cases of recurrent encephalopathy are known.

Side effects of bismuth preparations (weakness, loss of appetite, nephropathy, gingivitis, arthralgia) are observed when the concentration of bismuth in the blood plasma is over 100 µg/l.

Side effects of sucralfate: constipation, diarrhea, nausea, dry mouth, gastralgia, drowsiness, dizziness, headache, pruritus, rash, urticaria, pain in the lumbar region. The appearance of drowsiness and convulsions is due to the toxic effect of aluminum.

Side effects of misoprostol: abdominal pain, flatulence, nausea, vomiting, diarrhea, constipation, lower abdominal pain (associated with contractions of the myometrium), dysmenorrhea, polymenorrhea, menorrhagia, metrorrhagia. Allergic reactions: skin rash, itching, angioedema. May be observed: changes in body weight, asthenia, increased fatigue; extremely rarely - convulsions (in women in the postmenopausal period). With caution, misoprostol is used in patients with arterial hypotension, lesions of the arteries of the heart and brain, epilepsy, hypersensitivity to prostaglandins or their analogues.

Interaction

De-nol * may cause a decrease in the absorption of tetracyclines, iron preparations, calcium. You should not drink milk half an hour before taking and half an hour later. Do not use other bismuth preparations or drink alcohol at the same time. Bismuth subsalicylate is not recommended to be administered simultaneously with anticoagulants, anti-gout agents and antidiabetic drugs.

With the simultaneous use of sucralfate with indirect anticoagulants, a decrease in their anticoagulant activity is possible. With simultaneous use, the absorption of fluoroquinolone derivatives decreases, and the absorption of amitriptyline also decreases, which may lead to a decrease in its clinical efficacy. It is believed that with the simultaneous use of sucralfate with amphotericin B, tobramycin, the formation of chelate complexes is possible, which can lead to a decrease in their antimicrobial activity.

With simultaneous use with digoxin, a decrease in its absorption is possible. It is believed that with simultaneous use, a slight decrease in the absorption of ketoconazole and fluconazole is possible. With simultaneous use with levothyroxine, the effectiveness of levothyroxine sodium is noticeably reduced. With simultaneous use with sucralfate, slight changes in the pharmacokinetics of theophylline were observed. It is also believed that a significant decrease in the absorption of theophylline from sustained release dosage forms is possible. It is believed that with simultaneous use, a decrease in the absorption of tetracycline is possible. With simultaneous use, the absorption of phenytoin, sulpiride decreases. A case of a decrease in the concentration of quinidine in the blood plasma with simultaneous use with sucralfate is described. With simultaneous use, it is impossible to exclude some decrease in the bioavailability of cimetidine, ranitidine, roxatidine.

With the simultaneous use of misoprostol with antacids, the concentration of misoprostol in the blood plasma decreases. With simultaneous use with magnesium-containing antacids, diarrhea may increase. With simultaneous use with acenocoumarol, a case of a decrease in the anticoagulant effect of acenocoumarol is described.

20.3. ANTIVOTE MEDICINES

Nausea is an unpleasant, painless, peculiar sensation that precedes vomiting. Vomiting is the reflex act of expelling the contents of the stomach through the mouth, while the diaphragm and external oblique muscles of the abdomen contract, creating positive pressure in both the abdominal and chest cavities. There is a relaxation of the upper esophageal sphincter, expansion of the abdominal esophagus and contraction of the pylorus, which contributes to a faster exit of food through the mouth. Vomiting is a protective physiological reaction that promotes the release of the stomach from toxic or indigestible products.

There are three types of vomiting:

Actually reflex vomiting associated with the pathology of the digestive system;

Toxic - with the accumulation in the body of exogenous poisons, or toxins, or drugs;

Central - with diseases or lesions of the central nervous system.

The so-called vomiting center is localized in the dorsal part of the lateral reticular formation of the medulla oblongata. except

In addition, there is a second area involved in the act of vomiting, the “chemoreceptor trigger zone”. It is located in the floor of the fourth ventricle of the brain. Afferent signals to the center of vomiting come from numerous peripheral areas, including the pharynx, heart, peritoneum, mesenteric vessels, and biliary tract. Stimulation of each of these zones can cause vomiting. Regardless of the cause that causes the gag reflex, neurotransmitters take part in its implementation: dopamine, histamine, acetylcholine, endogenous opiates, serotonin, GABA, substance P. The pharmacological effect on some of these substances is the basis for the creation of many antiemetic drugs.

Mechanism of action and main pharmacodynamic effects(See details for each drug group.)

Classification

In the group of antiemetic drugs there are drugs of various chemical nature. According to the pharmacological effect, they can be divided into several subgroups:

Centrally acting drugs that block serotonin receptors: granisetron, ondansetron, tropisetron;

Centrally acting drugs that block dopamine receptors: domperidone, metoclopramide, sulpiride;

Centrally acting drugs that block dopamine and cholinergic receptors: thiethylperazine.

Centrally acting drugs that block serotonin receptors. Ondansetron selectively blocks the serotonin 5-HT3 receptors of neurons, eliminating nausea and vomiting caused by the release of serotonin. It is used against the background of treatment with cytostatic drugs, with radiation therapy, in the postoperative period.

Tropisetron, like ondansetron, is a competitive serotonin 5-HT3 receptor antagonist in peripheral tissues and the central nervous system. It blocks the gag reflex caused by chemotherapeutic anticancer drugs that stimulate the release of serotonin from enterochromaffin-like cells of the mucous membrane of the stomach and intestines. Hydroxylated with subsequent conjugation with glutathione in the liver; metabolites of this process are inactive. The duration of action of the drug is up to 24 hours, it is excreted from the body slowly.

Granisetron is considered a 5-HT3 receptor antagonist with a high degree selectivity.

Centrally acting drugs that block dopamine receptors. The effect is due to the central dopamine blocking action. These drugs act on brainstem trigger points to regulate gastric and intestinal motility without affecting gastric secretion, thus exerting an antiemetic effect, soothing hiccups and eliminating nausea.

Metoclopramide, domperidone and sulpiride, in some situations, relieve nausea, vomiting caused by apomorphine, morphine, but are ineffective in vomiting caused by cytostatics. These drugs inhibit the production of gastrin in response to eating meat food, have a vasodilating effect, improve blood flow in the abdominal organs, and enhance reparative processes. Sulpiride also has a moderate antiserotonin effect.

Metoclopramide and sulpiride to a greater extent reduce the motor activity of the esophagus, accelerate gastric emptying, activate the esophageal-gastric sphincter, increase the activity of the pyloric part of the stomach, duodenal motility. Metoclopramide accelerates the movement of food through the small intestine without significantly increasing peristalsis and without causing diarrhea. Cholinomimetic effects of metoclopramide and sulpiride are limited to the proximal intestine, eliminated by anticholinergics and morphine.

Centrally acting drugs that block dopamine and cholinergic receptors. Thiethylperazine acts on the chemoreceptor trigger zone and on its own center of vomiting, providing a central antiemetic effect. It has adreno- and m-anticholinergic action; binds dopamine receptors in the nigrostriatal pathways, but, unlike neuroleptics, it does not have antipsychotic and cataleptogenic properties.

Pharmacokinetics

When administered orally, the bioavailability of ondansetron reaches 60%; C max - 1.5 h; up to 70-76% of the drug binds to plasma proteins. T 1/2 with parenteral administration - 3 hours. It is excreted in the urine. Contraindicated in patients with hypersensitivity to the drug and in the first trimester of pregnancy.

After rapid intravenous administration of 20 or 40 mcg/kg of granisetron, its mean peak plasma concentration is 13.7 and 42.8 mcg/L, respectively. Plasma protein binding is 65%. The drug is rapidly metabolized by demethylation and oxidation. The half-life is 3.1-5.9 hours, in cancer patients it rises to 10-12 hours.

urine and feces, mainly in the form of conjugates, 8-15% of the drug is found in the urine unchanged.

Tropisetron is absorbed from the intestine within 20 minutes (more than 95%). Cmax is achieved within 3 hours. Up to 70% of the drug binds to plasma proteins.

Metoclopramide is rapidly absorbed from the gastrointestinal tract, bioavailability is 60-80%, Cmax is reached after 1-2 hours. The time to reach maximum plasma concentration is 30-120 minutes. It is excreted through the kidneys in unchanged form (about 30%) and in the form of conjugates. The half-life is from 3 to 5 hours, with impaired renal function it increases to 14 hours. It penetrates through the BBB, the placental barrier, into breast milk.

Domperidone is rapidly absorbed when taken orally on an empty stomach. C max in plasma is reached within about 1 hour. The low absolute bioavailability of domperidone when administered orally (approximately 15%) is due to extensive primary metabolism in the intestinal wall and liver. Hypoacidity of gastric juice reduces the absorption of domperidone. When taken orally, domperidone does not accumulate and does not induce its own metabolism. C max in plasma 90 minutes after administration, equal to 21 ng / ml, after a 2-week intake of 30 mg / day was almost the same as after taking the first dose (18 ng / ml). Domperidone is 91-93% bound to plasma proteins. The drug is metabolized in the liver by hydroxylation and N-dealkylation. In drug metabolism studies in vitro using diagnostic inhibitors, it was found that CYP3A4 is the main isoenzyme of the cytochrome P-450 system involved in the process of N-dealkylation of domperidone, while CYP3A4, CYP1A2 and CYP2E1 are involved in the process of aromatic hydroxylation of domperidone. Excretion in urine and feces is 31% and 66% of the oral dose, respectively. It is excreted unchanged in the feces - 10% and in the urine approximately 1%. T 1 / 2 from blood plasma after taking a single dose is 7-9 hours in healthy people. In patients with severe renal insufficiency, T 1 / 2 increases to 20.8 hours.

Thiethylperazine after oral administration is well absorbed from the gastrointestinal tract. The maximum plasma concentration is after 2-4 hours. The volume of distribution is 2.7 l / kg. The drug is metabolized in the liver. T 1 / 2 about 12 hours. Approximately 3% of the dose is excreted unchanged.

Indications for use and dosage regimen. Antiemetics are indicated for symptomatic treatment nausea and vomiting. Centrally acting drugs that block serotonin receptors, given their mechanism of action, are used for nausea.

nausea and vomiting that developed during chemotherapy oncological diseases, for the prevention and treatment of vomiting after anesthesia.

Centrally acting drugs that block dopamine receptors are used:

With nausea, vomiting;

With postoperative atony of the intestine;

With hypokinetic emptying of the stomach;

With reflux esophagitis;

As part of complex therapy peptic ulcer;

With dyskinesia biliary tract;

With flatulence, hiccups;

With vomiting that has developed against the background of toxemia, radiation therapy, dietary disorders, taking drugs, with x-ray examinations, endoscopies.

Table 20-7. Dosing regimen of antiemetic drugs

Side effects and contraindications

When using ondansetron and tropisetron, headache, dizziness, diarrhea, and constipation may occur. These drugs are contraindicated in pregnancy and lactation, ondansetron is contraindicated, and tropisetron is not recommended for use in children.

When taking ondansetron, you may:

Pain in chest(in some cases with depression of the segment ST);

arrhythmias;

Arterial hypotension, bradycardia;

hiccups, dry mouth;

Transient asymptomatic increase in serum transaminase activity;

Spontaneous movement disorders, convulsions;

Urticaria, bronchospasm, laryngospasm, angioedema, anaphylaxis;

Flushing of the face, feeling of heat;

Temporary impairment of visual acuity;

Hypokalemia.

When taking tropisetron in patients with arterial hypertension may rise arterial pressure; in rare cases, visual hallucinations are possible. When using granisetron, a transient increase in the activity of liver enzymes (transaminases) in the blood, constipation, headache, skin rash are possible. The drug is contraindicated in case of hypersensitivity to it.

When taking metoclopramide, sometimes there is a feeling of fatigue, headaches, dizziness, anxiety, depression, drowsiness, tinnitus, agranulocytosis, children may develop a dyskinetic syndrome (involuntary tic-like twitching of the muscles of the face, neck or shoulders). Perhaps the appearance of extrapyramidal disorders. In isolated cases, a severe neuroleptic syndrome develops. With long-term treatment with metoclopramide, parkinsonism may develop. From the cardiovascular system: supraventricular tachycardia, hypotension, hypertension. From the gastrointestinal tract: constipation, diarrhea, dry mouth. From the endocrine system: gynecomastia, galactorrhea or disorders menstrual cycle. With the development of these phenomena, metoclopramide is canceled. Metoclopramide is contraindicated in case of hypersensitivity to the drug, pheochromocytoma, intestinal obstruction, intestinal perforation and gastrointestinal bleeding, prolactin-dependent tumor, epilepsy and extrapyramidal movement disorders, in the first trimester of pregnancy and

lactation period, children under 2 years. Use with caution in arterial hypertension, bronchial asthma, impaired liver function, hypersensitivity to procaine and procainamide, children aged 2 to 14 years. During the II and III trimester of pregnancy, the drug is prescribed only for health reasons. In patients with reduced kidney function, the drug is prescribed in reduced doses.

When taking domperidone, transient intestinal spasms may develop (completely reversible and disappear after stopping treatment). Rarely develop extrapyramidal symptoms in children, in isolated cases - reversible extrapyramidal symptoms in adults. In case of violation of the functions of the blood-brain barrier, the possibility of neurological side effects is completely excluded. Hyperprolactinemia, galactorrhea, gynecomastia are possible. Allergic reactions: rash and urticaria. Domperidone is contraindicated in gastrointestinal bleeding, mechanical obstruction, or perforations in which stimulation motor function stomach can be dangerous, with a prolactin-secreting pituitary tumor (prolactinoma), hypersensitivity to the components of the drug. The use of domperidone in the first trimester of pregnancy is not desirable. With caution, the drug is prescribed to patients with hepatic insufficiency, given the high degree of metabolism of domperidone in the liver.

When taking thiethylperazine, dry mouth, dizziness may occur; with prolonged use, extrapyramidal disorders and liver dysfunction are possible. The drug is contraindicated in children under 15 years of age, with depression, coma, acute attack of glaucoma, severe liver and kidney failure, hypersensitivity to phenothiazine drugs.

Interaction

It should be borne in mind that ondansetron is metabolized by the liver cytochrome P-450 enzyme system. Therefore, ondansetron-lance should be administered with caution simultaneously with cytochrome P-450 inducers (CYP2D6 and CYP3A) - barbiturates, carbamazepine, carisoprodol, aminoglutethimide, griseofulvin, nitrous oxide *, papaverine, phenylbutazone, phenytoin (probably with other hydantoins), rifampicin , tolbutamide; with inhibitors of cytochrome P-450 (CYP2D6 and CYP3A) - allopurinol, antibiotics of the macrolide group (including erythromycin), antidepressants (MAO inhibitors), chloramphenicol, cimetidine, oral contraceptives containing estrogens, diltiazem, disul-

firam, valproic acid, sodium valproate, fluconazole, fluoroquinolones, isoniazid, ketoconazole, lovastatin, metronidazole, omeprazole, propranolol, quinidine, quinine, verapamil.

With the simultaneous administration of tropisetron with rifampicin, phenobarbital or other drugs that induce microsomal liver enzymes, its plasma concentration decreases and the antiemetic effect decreases.

No specific drug interactions with granisetron not noted.

Metoclopramide reduces the effect of anticholinesterase agents, enhances the absorption of antibiotics (tetracycline, ampicillin), paracetamol, levodopa, lithium and alcohol, reduces the absorption of digoxin and cimetidine, enhances the effect of drugs that depress the central nervous system. Antipsychotic drugs should not be given concomitantly with metoclopramide in order to avoid a possible increase in extrapyramidal disorders. The drug can affect the action of tricyclic antidepressants, MAO inhibitors and sympathomimetic agents, reduces the effectiveness of therapy with H2-histamine blockers, increases the risk of developing hepatotoxicity when combined with hepatotoxic agents, reduces the effectiveness of pergolide, levodopa, increases the bioavailability of cyclosporine, which may require control of its concentration, increases bromocriptine concentration.

Anticholinergics, cimetidine, sodium bicarbonate* can neutralize the effect of domperidone. Antacids and antisecretory drugs should not be taken concomitantly with motilium*, as they reduce its bioavailability (after ingestion). The main pathway of metabolic transformations of domperidone occurs with the participation of the CYP3A4 isoenzyme of the cytochrome P-450 system. Based on research in vitro it can be assumed that with the simultaneous use of domperidone and drugs that significantly inhibit this isoenzyme, it is possible to increase the level of domperidone in plasma. Examples of inhibitors of the CYP3A4 isoenzyme are the following drugs: azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone. Theoretically, since domperidone has a gastrokinetic effect, it could affect the absorption of drugs when taken orally, in particular drugs with a sustained release of the active substance or enteric-coated drugs. However, the use of domperidone in patients receiving paracetamol or

selected therapy with digoxin did not affect the level of these drugs in the blood. Motilium can also be combined with antipsychotics, the action of which it does not enhance; dopaminergic receptor agonists (bromocriptine, levodopa), whose undesirable peripheral effects, such as digestive disorders, nausea, vomiting, it suppresses without neutralizing their main properties.

Thiethylperazine potentiates the action of alcohol, benzodiazepines, narcotic analgesics and other drugs that depress the functions of the central nervous system.

20.4. ENZYME PREPARATIONS

An indication for the appointment of enzyme preparations for patients with diseases of the gastrointestinal tract is the syndrome of maldigestion and malabsorption of various origins with or without exocrine pancreatic insufficiency. Disorders of abdominal digestion are observed with alimentary errors, dysfunction and diseases of the stomach, small intestine, pancreas, liver, biliary tract, or with combined pathology. First, there are disorders of parietal digestion, and then absorption (malabsorption). Clinical manifestations of digestive disorders are caused by symptoms of dyspepsia of varying severity. Most often, patients are worried about flatulence, somewhat less often - unstable stools. Clinical signs of exocrine pancreatic insufficiency include pain in the umbilical region, decreased appetite, flatulence, unstable stools, steatorrhea, creatorrhoea, nausea, recurrent vomiting, general weakness, weight loss, decreased physical activity, stunting (in severe forms).

Enzyme preparations are multicomponent medicines, which are based on a complex of enzymes of animal, vegetable or fungal origin in pure form or in combination with auxiliary components (bile acids, amino acids, hemicellulase, simethicone, adsorbents, etc.).

Preparations containing enzymes of the gastric mucosa.

Pepsin is a preparation containing a proteolytic enzyme. It is obtained from the mucous membrane of the stomach of pigs. Tablets of acidinpepsin * (analogues: betacid *, acipepsol *, pepsamine, pepsacid) contain 1 part of pepsin and 4 parts of betaine (acidin *). When administered to the stomach, betaine hydrochloride is hydrolyzed and separates free

hydrochloric acid. Pepsidil* is a solution in hydrochloric acid of the products of enzymatic hydrolysis of the gastric mucosa of pigs containing pepsin. Abomin* contains a sum of proteolytic enzymes. It is obtained from the gastric mucosa of calves and lambs of milk age.

Preparations containing pancreatic enzymes or similar. Enzymatic drugs of this group contain digestive enzymes of the pancreas (Table 20-8).

Table 20-8. Digestive enzymes of the pancreas

* Enzymes are secreted by the pancreas in an inactive form (proenzymes); they are activated in the duodenum.

Enzyme preparations containing or similar to pancreatic enzymes:

Pancreatin (trypsin, α-amylase*, lipase);

Creon 10000, Creon 25000 * (pancreatin);

Orase* (amylase, maltase, protease, lipase);

Solizyme* (lipolytic enzyme from culture Penicillium solitum);

Somilase* (solyzyme*, α-maltase);

Nigedase* (lipolytic enzyme from vegetable raw materials);

Panzinorm forte H * (bile extract, pancreatin, amino acids from the glands of cattle);

Pankurmen* (amylase, lipase, protease, corn extract);

Festal * (amylase, lipase, protease, hemicellulose, bile components);

Digestal* (pancreatin, bile extract, hemicellulose);

Enzistal* (pancreatin, hemicellulose, bile extract);

Mezim forte * (pancreatin, amylase, lipase, protease).

All enzyme drugs differ in enzyme activity, their composition and exist in different dosage forms. In some cases, these are single-layer tablets, soluble only in the intestines, in others - two-layer, for example, panzinorm forte H *. Its outer layer dissolves in the stomach, contains an extract of the gastric mucosa and amino acids, and the second shell is acid-resistant, dissolves in the intestines, contains pancreatin and cattle bile extract.

Along with the enzymes of the pancreas and stomach, the combined enzyme preparation often includes hemicellulose, which promotes the breakdown of plant membranes, which reduces fermentation processes and reduces the formation of gases in the intestine (festal *) (Table 20-9).

Table 20-9. The composition of the main enzyme preparations

Preparations containing enzymes of plant origin.

An enzyme of plant origin used to correct maldigestion, malabsorption and exocrine insufficiency

pancreas, consider papain (pepfiz *, unienzyme *). Papain - a proteolytic enzyme present in melon tree latex (Carica papaya L.). It is able to hydrolyze almost any peptide bonds, with the exception of those formed by proline residues. Sometimes this group of drugs includes bromelain.

In addition, the preparations may include fungal diastase (α-amylase), which breaks down polysaccharides (starch, glycogen) into simple disaccharides (maltose and maltotriose), substances that reduce flatulence (simethicone, activated carbon). Simethicone promotes coalescence (foam breakdown).

Sometimes combined preparations containing pancreatin in combination with plant enzymes (wobenzym *) are used.

20.5. Cholagogue, hepatoprotective, cholelitholytic drugs

This group of drugs includes drugs that can affect the formation of bile and its evacuation, perform protective functions in relation to the hepatocyte, and prevent the development of cholelithiasis. For a more complete understanding of the mechanism of their action, it is necessary to assess the physiological characteristics of bile secretion, the functions of the hepatocyte and gallbladder.

Hepatocytes - the main subunits of the liver, are separated from the bile capillaries by the so-called basolateral membrane, and from the sinusoids - by the sinusoidal membrane. The main function of the basolateral membrane is considered to be the secretion of bile into the bile capillaries, from which it enters the terminal bile ducts. From them, bile enters the larger ducts, then into the intralobular ducts, from where it enters the common bile duct, the gallbladder and the duodenum. Specific enzymes are located on this membrane: alkaline phosphatase, leucine aminopeptidase, γ-glutamyl transpeptidase.

Transport processes are carried out through the sinusoidal membrane: the capture of amino acids, glucose, organic anions (bile, fatty acids and bilirubin) for subsequent intracellular reactions. On the sinusoidal membrane of the hepatocyte, specific transporters are located, in particular Na +, K + -ATPase, and the processes of release of albumin, lipoproteins and blood coagulation factors occur.

Bile (the so-called primary, or portion "C") is a liquid with an osmotic pressure equal to that

in blood plasma, and is a product of exocrine secretion of the liver. In a normally functioning organ, it is secreted constantly and its daily volume ranges from 250 to 1000 ml. Bile contains many components that determine its functional role in digestion:

Inorganic substances: bicarbonates, chlorides and phosphates of sodium, potassium, calcium, magnesium, iron and other metals;

Organic compounds: primary bile acids (cholic, chenodeoxycholic); secondary bile acids (deoxycholic, lithocholic); cholesterol; phospholipids; fatty acid; protein; urea, uric acid;

Vitamins A, B, C;

Some enzymes: amylase, phosphatase, proteases, catalase, etc. The formation of bile consists of three stages.

1st stage. Capture from the blood of the bile acids contained in it, bilirubin, cholesterol, etc.

2nd stage. Metabolism and synthesis of new components of bile.

3rd stage. The release of all components through the biliary membrane into the bile ducts, then into the subsequent ducts and the duodenum.

In the intestines, bile is involved in the hydrolysis of fats to prepare them for absorption. In addition, bile activates pancreatic lipase, inhibits the action of gastric proteases, and regulates intestinal motility. It has mild bactericidal properties, but salmonella and most viruses can remain in it for a long time.

The gallbladder concentrates and stores bile between meals. It also evacuates bile by contracting smooth muscle wall elements in response to cholecystokinin stimulation and maintains hydrostatic pressure in the bile ducts.

Choleretic drugs

Drugs that affect and normalize bile secretion (choleretic drugs) are usually divided into three groups: choleretics, cholekinetics and myotropic antispasmodics.

Choleretics. The mechanism of action of choleretics is associated with reflex reactions with the mucous membrane of the predominantly small intestine when exposed to bile acids or substances containing essential oils.

This group includes:

Preparations containing bile acids;

Synthetic preparations;

drugs of plant origin;

Mineral water.

Choleretics containing bile acids include allochol *, lyobil *, cholenzym *, panzinorm forte-N *, festal *, decholine, cholagol *. Allochol * contains condensed bile, thick garlic extract, thick nettle extract, activated charcoal. The action of the drug is based on stimulation of the secretory function of the liver and the same function of the intestine, increased peristalsis of the stomach and intestines, and the impact on the abnormal microflora of the colon. The use of the drug in acute liver diseases, jaundice or individual intolerance is not indicated. Lyobil * contains 0.2 g of lyophilized ox bile. Bile preparations enhance the formation of bile, stimulate its outflow, increase the secretion of pancreatic juice, and stimulate intestinal motility. Cholenzym * contains dry bile 0.1 g, dried pancreas 0.1 g, mucous membranes of the small intestines of slaughter cattle dried 0.1 g. stimulation of the digestive process.

Synthetic choleretics include hymecromon, osalmid, nikodin *, cyclovalone, etc. Hymecromon excites the receptors of the intestinal mucosa and thereby enhances the secretion of bile. The drug increases the osmotic gradient between bile and blood, which leads to an increase in the filtration of electrolytes and water into the bile ducts, a decrease in the content of cholates and counteraction to stone formation. Hymecromon, in addition, is a myotropic antispasmodic and acts on the biliary tract and their sphincters, does not stimulate the motility of the gallbladder and ducts. The drug also does not act on the smooth muscles of the vessels and intestines. It is absorbed quickly, binds poorly to blood proteins, undergoes metabolism in the liver, and is excreted mainly through the intestines. The drug is used for dyskinesia of the gallbladder and biliary tract, cholecystitis, uncomplicated cholelithiasis and hepatitis with cholestasis. Its use is not indicated for patients with hypersensitivity to hymecromon, with exacerbation of peptic ulcer of the stomach and duodenum, with a violation of blood clotting. During treatment, diarrhea, abdominal pain, headache sometimes occur, blood clotting is disturbed.

Choleretics of plant origin include aloe tree *, common barberry *, valerian officinalis *, common oregano *, St.

min * , convaflavin * , berberine bisulfate *, etc. Flamin * - dry immortelle concentrate containing a sum of flavonoids. The choleretic effect is quite pronounced. Corn stigmas* (stigma bollards harvested during corn cob maturity) contain sitosterol, stigmasterol, fatty oils, essential oil, saponins and others active substances. It has been established that during treatment with corn preparations, bile secretion increases, its viscosity and relative density decrease, and the content of bilirubin decreases. Berberine bisulfate * - an alkaloid berberine, found in the roots and leaves of the common barberry, according to chemical structure refers to derivatives of isoquinoline, referred to Quaternary ammonium bases. In addition to hypotensive, it has a pronounced choleretic agent and is used in chronic hepatitis, cholecystitis. A tincture of the leaves of the Amur barberry also has a choleretic effect.

Mineral waters containing mainly bicarbonates, sulfates, chlorine and magnesium (Essentuki No. 4 and No. 17, Jermuk, Slavyanovskaya, Smirnovskaya, Narzan Kislovodsky, Naftusya, Mirgorodskaya, Moscow, Sochi, Rostov, Smolenskaya, etc.) also have choleretic activity.

Cholekinetics. The effect of cholekinetics is associated with an increase in the tone of the gallbladder and a decrease in the tone of the biliary tract and the sphincter of Oddi. Almost all cholekinetics have a certain cholesecretory activity and anti-inflammatory effect. These include plant-derived cholekinetics and synthetic cholekinetics.

Cholekinetics of plant origin: berberine bisulfate * and others.

Synthetic cholekinetics: osalmide, hydroxymethylnicotinamide (Nicodin*), phenipentol (Febichol*). Osalmid stimulates the formation and secretion of bile, reduces its viscosity, has an antispasmodic effect on the smooth muscles of the bile ducts, including sphincters, has hypocholesterolemic properties, and normalizes the content of bilirubin. Hydroxymethylnicotinamide, in addition to choleretic, has an antimicrobial effect. The drug enhances the formation and secretion of bile. The antimicrobial effect is due to the elimination of the formaldehyde part of the molecule in the intestine. The other part, nicotinamide, implements vitamin PP activity. Formaldehyde binds to electrophilic substrates, including microbial cells, coagulates them, and nicotinamide repeats the path of vitamin PP in the body and stimulates bile secretion. Phenipentol is predominantly a choleretic drug. It excites receptors

intestinal mucosa and reflexively stimulates hepatic secretion, increasing the amount of bile secreted, the content of cholesterol and bile acids in it, thereby optimizing the osmotic gradient between bile and blood. In addition, the drug enhances the osmotic filtration of water and electrolytes into the bile ducts, inhibits the formation of gall and cholesterol stones, stimulates the motility of the stomach and intestines. Not indicated for acute diseases of the liver, gallbladder, obstructive jaundice.

Myotropic antispasmodics, such as papaverine, drotaverine (noshpa *), benziklan (galidor *), pinaverium bromide (dicetel *), otilonium bromide, trimebutine (debridate *), are able to inhibit phosphodiesterase and block adenosine receptors. These processes change the ionic balance and reduce the accumulation of calcium in smooth muscle cells. These effects lead to a decrease in motor activity of smooth muscles. Benciclane, in addition to its action on smooth muscle internal organs, has moderate vasodilating and sedative effects, local anesthetic activity. When taken orally, it is rapidly and completely absorbed. The maximum plasma concentration is reached after a single dose within the first three hours. The half-life is six hours, it is eliminated mainly in the urine (97%) as inactive metabolites. May cause dizziness, headache, agitation, dry mouth, nausea, anorexia, diarrhea, tachycardia. Pinaverium bromide lowers the increased tone of the smooth muscles of the intestines and biliary tract. Sometimes contributes to the appearance of dyspeptic phenomena. Otilonium bromide selectively relaxes the smooth muscles of the gastrointestinal tract. When taken orally, about 5% of the dose is absorbed, excreted mainly in the bile and excreted in the feces. Use with caution in glaucoma and during pregnancy.

For rapid relief of pain in biliary dyskinesia, nitrates are used, but they are of little use for long-term course treatment due to cardiovascular effects and other side effects.

Hepatoprotective agents

Hepatoprotective agents are drugs that increase the resistance of hepatocytes to pathological influences and enhance the neutralizing functions of the liver. These include:

Lipid peroxidation inhibitors;

Essential phospholipids;

Herbal preparations.

Lipid peroxidation inhibitors- thioctic acid (α-lipoic acid*, berlition 300*, thiogamma*, thioctacid 600T*, espa-lipon*). Thioctic acid is a coenzyme for the oxidative decarboxylation of pyruvic acid and α-keto acids, normalizes energy, carbohydrate and lipid metabolism, and regulates cholesterol metabolism. With course treatment improves liver function, reduces the damaging effect of toxic exogenous and endogenous agents. The drug is rapidly absorbed from the intestine; C max is achieved after 50 minutes. Bioavailability is about 30%, it is oxidized and conjugated in the liver. It is excreted mainly by the kidneys in the form of inactive metabolites (80-90%); T 1/2 is 20-50 min. The total plasma clearance is 10-15 ml / min. Sometimes the drug causes hypoglycemia, allergic reactions; incompatible with Ringer's and glucose solutions. Overdose may cause headache, nausea, vomiting.

Essential phospholipids be contained in the Essentiale preparation (Essentiale H*, Essentiale forte H*). One capsule of the drug contains "essential" phospholipids 300 mg, thiamine mononitrate 6 mg, riboflavin 6 mg, pyridoxine hydrochloride * 6 mg, cyanocobalamin 6 μg, nicotinamide 30 mg, tocopherol acetate * 6 mg. The phospholipids contained in the preparation are diglycerine phospholipids of cholinergic acid, linoleic, linolenic and other unsaturated fatty acids. Since these substances are considered the main elements of the cellular structure of the hepatocyte, together with the vitamins included in the drug during course treatment, they normalize liver metabolism, improve its detoxification function, optimize microcirculation in the liver, reduce jaundice, and positively affect the lipid spectrum of blood plasma.

TO hepatoprotectors of plant origin include, first of all, drugs containing milk thistle alkaloids [hepatofalk planta, silibinin (karsil*), legalon 70* (silymarin*)], one of which, silibinin, has pronounced hepatoprotective and antitoxic properties. The mechanism of cytoprotection is associated with the suppression of lipid peroxidation that damages the membranes of liver cells. If the hepatocyte is already damaged, silibinin stimulates the synthesis of proteins and phospholipids that restore the composition and physicochemical properties of cell membranes. Silibinin prevents the development of fibrosis, prevents the penetration of certain hepatotoxic poisons into the liver cell.

Absorption of silibinin is low. It undergoes enterohepatic circulation. Metabolized in the liver by conjugation, T 1/2 ra-

veins 6 hours, excreted mainly with bile in the form of glucuronides and sulfates. Does not accumulate. The drug is not indicated for patients with hypersensitivity to its components. Silibilin can sometimes cause diarrhea. Legalon 70*; one tablet contains silymarin* 70 mg with a minimum of 30 mg silibinin in 90 mg milk thistle fruit extract (Carduus marianus, syn. Silybum marianum). Hepatofalk Planta contains in one capsule a dry extract of milk thistle, an extract of greater celandine and Javanese turmeric.

Cholelitholytic agents

It is known that cholesterol dissolves in bile under the action of bile acids. In cases where the cholesterol content exceeds the content of bile acids and lecithin, the process of its crystallization and the formation of gallstones is possible, and one of the ways to combat stone formation is considered to be a decrease in its concentration in bile. A positive cholelitholytic effect (the ability to dissolve gallstones) with a sufficiently long course of use is possessed by chenodeoxycholic acid and ursodeoxycholic acid, which have a modified structure of bile acids.

These drugs increase the hydrophilicity of bile. They prevent crystallization and precipitation of cholesterol and contribute to the dissolution of cholesterol stones. Since inflammatory processes in the gallbladder contribute to the crystallization of cholesterol and the violation of the mineral composition of bile, the use of antimicrobial agents in these cases is the prevention of cholelithiasis.

Chenodeoxycholic and ursodeoxycholic acids are produced semi-synthetically from animal bile at the expense of chenodeoxycholic, ketolithocholic and other bile acids. The drugs inhibit the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase, which reduces the total synthesis of cholesterol due to the substrate block of its hepatic metabolism, facilitates the work of the liver and promotes the excretion of cholesterol from the body. At the same time, cholesterol not only does not precipitate in the biliary tract, but also dissolves from already formed stones. At a dose of 20 mg/kg per day (for three doses, after meals), chenodeoxycholic acid is able to dissolve cholesterol-containing stones in the gallbladder at a rate of 0.5-1.0 mm (in diameter) per month.

For cholelitholytic therapy, the following conditions are necessary:

Stones in the gallbladder should be only cholesterol and no more than 2 cm in diameter;

The usefulness of the contractile function of the gallbladder with a volume of gallstones less than 30% of the volume of the gallbladder;

The absence of contraindications for such therapy: active hepatitis and cirrhosis of the liver, peptic ulcer of the stomach and duodenum, kidney damage;

The duration of the treatment course is from 4 months to 2 years.

20.6. PROTEOLYSIS INHIBITORS

Drugs that inhibit proteolytic enzymes in plasma and tissues include aprotinin (gordox *, contrykal *, trasylol 500,000 *). This drug inhibits the activity of trypsin, plasmin and other proteases, which leads to a decrease in the activity of the Hageman factor and blocking the transition of kallikreinogen to kallikrein. The above biologically active substances contribute to the development of severe necrotic changes in the pancreas during its acute inflammation. The consequence of the action of antienzymes is the suppression of the formation of kinins (bradykinin in the blood plasma and kallikrein in the tissues), which cause microcirculation disorders, vasodilation, and increase vascular permeability.

Aprotinin is a substance of a polypeptide nature, a pancreatic trypsin inhibitor. It is obtained from the lungs of cattle. Inhibits proteolytic enzymes: trypsin, chymotrypsin, kallikrein, including activating fibrinolysis - plasmin. It is used to treat patients with acute pancreatitis, with hyperfibrinolytic bleeding, for the treatment and prevention of various forms of shock (endotoxic, traumatic, hemolytic).

After intravenous administration, the drug is rapidly distributed in the extracellular space. Briefly accumulates in the liver. The elimination half-life from blood plasma is about 150 minutes. It breaks down under the action of lysosomal enzymes of the kidneys and is excreted in the urine.

20.7. MEDICINES USED FOR DIARRHEA

Diarrhea (diarrhea) - frequent or single bowel movements with the release of liquid feces more than 250 g / day. Any diarrhea is a clinical manifestation of impaired absorption of water and electrolytes in the intestine. Four mechanisms are involved in the pathogenesis of diarrhea: intestinal hypersecretion, increased osmotic pressure

leniya in the intestinal cavity, violation of the transit of intestinal contents and intestinal hyperexudation. Diarrhea is considered acute if its duration does not exceed 2-3 weeks, and chronic if it lasts 4-6 weeks or more.

Due to the diversity of the etiology and pathogenesis of diarrhea in therapeutic practice, a very significant number of drugs are used, which are diverse both in chemical structure and in the mechanism of action. The tactics of their use depends on the severity of the underlying and concomitant diseases in this patient. Below are the characteristics of the main groups of drugs used in the treatment of patients with diarrhea.

Antibacterial drugs, such as intetrix *, nifuroxazide (ersefuril *), dipendal-m, enterosediv *, are used for diarrhea of ​​bacterial etiology. Intetrix * contains tiliquinol n-dodecyl sulfate, tilbroquinol; dependal-m - furazolidone and metronidazole; enterosediv * - streptomycin, menadione sodium bisulfite and sodium citrate.

Bacterial preparations such as bactisubtil * , enterol * , hilak forte * also have antidiarrheal activity. Bactisubtil* is a bacterial culture IP-5832 in the form of spores, calcium carbonate, white clay, titanium oxide and gelatin; enterol * contains lyophilized culture Saecharamyces doulardii; hilak forte * contains a sterile concentrate of metabolic products of normal intestinal microflora: lactic acid, lactose, amino acids, fatty acids.

adsorbents. Smectite (smectite) contains dioctahedral smectite, which has strong adsorbing properties. The drug stabilizes the mucous barrier, replenishing its defects, forming polyvalent bonds with mucus glycoproteins; protects the mucous membrane of the stomach and intestines from the negative effects of hydrogen ions, hydrochloric acid, bile salts, viruses, bacteria, and other aggressive factors.

Attapulgite (kaopektate *) - natural purified aluminum-magnesium silicate in colloidal form (natural mixture from the group of palygorskite minerals). It has antidiarrheal, adsorbing, enveloping healing properties. After ingestion, it is not absorbed, forms a kind of film on the mucous membrane of the stomach and intestines. Adsorbs liquid, toxic substances, bacteria, reduces inflammation, normalizes intestinal flora. Not indicated for children under 6 years of age, persons with hypersensitivity to this drug or patients with amoebic dysentery. When used with other drugs, it may interfere with their absorption.

Tannacomp* contains tannin albuminate, ethacridine lactate. It has astringent, antimicrobial, antidiarrheal and anti-inflammatory effect. It is especially indicated in the treatment of patients with nonspecific diarrhea (traveler's diarrhea, change in diet, sudden change in climatic conditions, etc.).

Regulators of motor activity of the stomach and intestines. Loperamide (imodium *) has antidiarrheal activity, interacts with opiate receptors of the longitudinal and circular muscles of the intestinal wall, inhibits the release of acetylcholine and prostaglandins. The drug slows down peristalsis and the movement of intestinal contents. About 40% of the dose received by the patient is absorbed in the intestine, up to 95% of the drug binds to plasma proteins. Cmax is reached after 5 hours. It does not penetrate the blood-brain barrier, it is metabolized in the liver, T 1 / 2 from 9 to 14 hours, it is excreted in the feces and urine. Not indicated for patients with hypersensitivity to the drug, with intestinal obstruction, in the first trimester of pregnancy. May cause headache, fatigue, stool retention.

Octreotide is a synthetic octapeptide analog of somatostatin. It is considered an inhibitor of the synthesis of active secretory agents, including peptides and serotonin. Helps reduce secretion and intestinal motility. After subcutaneous administration, it is rapidly absorbed, C max up to 5.2 mg / ml at a dose of 100 μg is achieved within 25-30 minutes, 65% of the administered dose is bound in plasma to lipoproteins and, to a lesser extent, to albumins. T 1/2 after injection is 100 minutes, the duration of action is about 12 hours. 32% of the unchanged drug is excreted in the urine. Contraindicated in pregnancy.

Medicinal plants: common anise *, sandy immortelle *, elecampane high *, common oregano *, St. licorice * , cudweed swamp * , common yarrow * , bilberry * , bird cherry * and others also have antidiarrheal activity.

20.8. LAXATIVE MEDICINES

Constipation refers to slow, difficult, infrequent or systematically incomplete emptying of the intestines with solid, usually fecal masses. The most common causes are violations of the processes of formation of fecal masses and their passage through the large intestine:

Disorder of motor function (dyskinesia) of the colon;

Weakening of the natural urge to defecate;

Changes anatomical structure colon or its surrounding tissues, preventing the normal movement of feces.

Constipation is divided into primary, secondary, idiopathic. The cause of primary constipation is anomalies, malformations of the colon and its innervation. The cause of secondary constipation are diseases and damage to the colon, as well as diseases of other organs and systems that occur with metabolic disorders. Idiopathic constipation is caused by impaired motility of the rectum and colon, the cause of which is unknown, for example, inert bowel, idiopathic megacolon.

From pathogenetic positions, constipation can be divided into three main types: alimentary, mechanical and dyskinetic.

In the treatment of patients with constipation, the following groups are used

Osmotic laxatives;

Medicines that inhibit the absorption of water from the intestines;

Synthetic laxatives;

Salt laxatives;

Means that cause an increase in the volume of feces;

Means softening fecal masses;

Medicines that stimulate intestinal transit.

osmotic laxatives, containing poorly absorbed carbohydrates: lactulose (normaze *, dufalac *) or high-molecular polymers that contribute to water retention - macrogol (forlax *). They increase the osmotic pressure of the chyme in the small intestine and promote the secretion of water into its lumen.

Lactulose - a synthetic polysaccharide, reduces the concentration of ammonium ions in the blood by 25-50% and reduces the severity of hepatogenic encephalopathy; stimulates the reproduction of lactic acid bacteria and peristalsis of the colon, acting as a laxative. In the intestine, lactulose is hydrolyzed to lactic and formic acids, and the osmotic pressure increases, the contents of the intestine are acidified, and its emptying improves. The action occurs 24-48 hours after administration; little is absorbed into the blood, about 3% of the administered dose of the drug is excreted in the urine. Lactulose is contraindicated in persons with increased sensitivity to this drug. As side effects, diarrhea, flatulence, excessive loss of electrolytes can be noted.

Macrogol (Forlax *) forms hydrogen bonds with water molecules in the intestinal lumen, increases the osmotic pressure in the intestine and the volume of fluid contained in it, enhances peristalsis and has a laxative effect. Not absorbed and not metabolized; the laxative effect occurs after 24-48 hours. Sometimes colicky pains in the lower abdomen and diarrhea may occur.

Medicines that inhibit the absorption of water from the intestines

and stimulating secretion by stimulating the chemoreceptors of the mucous membrane of the large intestine (antraglycosides). These include preparations of senna leaves * (sennosides A and B; bekunis *, regulax *, tisasen *) and sabura, rhubarb root *, laxative buckthorn fruits, alder buckthorn bark, castor oil.

Senna preparations contain the sum of anthraglycosides from the leaves of senna acutifolia and angustifolia. The laxative effect is due to inhibition of the absorption of sodium ions, water and stimulation of the secretion of sodium and water into the intestinal lumen due to an increase in the concentration of prostaglandin E 2 in its wall. This leads to an increase in the volume of intestinal contents and an increase in intestinal motility. After ingestion, the effect develops after 8-10 hours. The drugs are not absorbed and do not have a resorptive effect.

Farsighted rhubarb roots contain anthraglycosides and tanoglycosides, as well as their free aglycones: reumemodin, chrysophanol, rhein and others; chrysophanoic acid, resins, dyes. The laxative effect occurs 8-10 hours after ingestion and is mainly due to emodin, rhein and chrysophanoic acid, which, by irritating the receptors of the large intestine mucosa, cause an increase in its peristalsis and a faster passage of feces.

Buckthorn laxative fruits (zhostera laxative fruits *) contain free and glycosidic-bound anthraquinones and anthranols: rhamnoemodin, rhamnokatartin; sugar, pectin; mucous, coloring substances; flavonoids; bitterness is non-glycoside. Rhamnocitrin, xanthoramnetin, kaempferol provide, in addition to laxative, and anti-inflammatory effect.

Alder buckthorn bark contains anthraglycosides: frangulin; klikofrangulin, frangulaemodin; chrysophanoic acid, as well as tannins, organic acids, essential oils, sugars, alkaloids. The laxative effect of buckthorn is primarily due to anthraglycosides and chrysophanic acid.

Castor oil is obtained from the seeds of the castor bean. When taken orally, it is broken down by lipase in the small intestine to form

ricinoleic acid, which causes irritation of the intestinal receptors, and throughout its entire length, and enhances peristalsis. The laxative effect occurs after 5-6 hours.

Synthetic laxatives. Bisacodyl (Dulcolax*) is a synthetic laxative that also has a carminative effect. This drug irritates the receptors of the colon mucosa, thereby increasing the production of mucus, accelerates and enhances peristalsis. Contraindicated in patients with acute inflammatory diseases of the abdominal cavity.

Sodium picosulfate (guttalax *) is hydrolyzed in the intestine under the influence of sulfate-producing bacteria and forms free diphenol (an active metabolite), which irritates the receptors of the colon mucosa and stimulates peristalsis. It is not absorbed, the laxative effect occurs after 6-12 hours. It is not recommended to prescribe to persons with hypersensitivity to senna preparations, with acute diseases of the digestive system. May cause intermittent colicky abdominal pain.

saline laxatives, such as sodium sulfate, magnesium sulfate, artificial Karlovy Vary salt *, being slowly absorbed from the intestine, change the osmotic pressure in its cavity, which leads to the accumulation of water, liquefaction of stool and increased propulsion. Some role is played by irritation of the receptors of the intestinal mucosa. Salt laxatives, unlike anthraglycosides, act throughout the intestine. They are also shown in food poisoning, as they slow down the flow of toxins into the blood.

Means that cause an increase in the volume of feces. These drugs include non-absorbable disaccharides (sorbitol), kelp * (laminaride *), methylcellulose, psyllium (fiberlak), calcium polycarbophil, bran, flaxseed. Laminaria * (seaweed) - brown algae, found in the form of thickets along the Far East coast, in the White and Black Seas. The laxative property is due to the ability of the algae to swell intensively in the intestinal lumen, increasing in volume, irritate the mucosal receptors and thereby help accelerate bowel emptying. The drug is not indicated for persons with hypersensitivity to iodine.

Stool softeners facilitate their passage through the intestines. To drugs from this group include vaseline*, almond*, olive oil*, norgalax*, sodium phosphate (Enimax epima*).

Medicines that stimulate intestinal transit. This group of drugs includes wheat bran, divisit, mucofalk *. Mu-

kofalk * - granules for the preparation of oral suspension with the smell of apple or orange. These are hydrophilic fibers from the outer shell of psyllium seeds. Hydrophilic fibers are capable of retaining water in quantities much greater than their mass. The drug prevents thickening of the intestinal contents and thereby facilitates bowel movements. Practically not absorbed.

20.9. PROKINETICS

Prokinetics - drugs that normalize the motor activity of the esophagus, stomach and intestines. These include the following drugs: metoclopramide, domperidone, cisapride, tegaserod and prucalopride (comparative characteristics are given in Tables 20-10).

Table 20-10. Comparative characteristics of the main prokinetic drugs

These drugs are most widely used for the following diseases:

Esophageal dyskinesia, reflux esophagitis;

Functional indigestion, non-ulcerative (functional) dyspepsia;

irritable bowel syndrome;

Antiperistaltic dyskinesia of the stomach and duodenum, accompanied by nausea and vomiting;

Postoperative disorders of the motor function of the stomach and intestines;

Organic diseases of the digestive system, in which secondary motor disorders begin to dominate in the clinical picture of the disease (gastritis, peptic ulcer, enteritis, colitis, cholecystitis, etc.).

Metoclopramide. The drug is a dopamine antagonist, normalizes impaired motor activity of the smooth muscle apparatus of the gastrointestinal tract, increases the tone of the lower esophageal sphincter, enhances the tone and amplitude of the peristaltic waves of the stomach, promotes the movement of intestinal contents in the upper sections of the small intestine, acts antispastically, helps to stop nausea and vomiting (see . above). Widely used for reflux esophagitis, functional motor disorders of the stomach and intestines.

Metoclopramide is rapidly absorbed from the intestine, reaching a maximum plasma concentration 1-2 hours after a single dose. Up to 30% of the drug binds to blood proteins, after which it is rapidly distributed throughout the tissues of the body. The effect persists for 1-2 hours; the half-life is about 5-6 hours. Up to 85% of metoclopramide is excreted in the urine.

Contraindications: hypersensitivity of the patient to the drug, glaucoma, pheochromocytoma, extrapyramidal disorders, pregnancy. With prolonged use of metoclopramide, dry mouth, diarrhea, increased drowsiness, extrapyramidal disorders, and sometimes skin rashes may occur.

Domperidone. The drug blocks central dopamine (D 2) receptors, increases the duration of peristaltic contractions of the antrum of the stomach and duodenum, normalizes the function of the lower esophageal sphincter, promotes the movement of gastric and intestinal contents, reduces the manifestations of nausea and vomiting (see above). It is used for violations of the motor activity of the esophagus, stomach and initial sections of the intestine. It has been shown that domperidone, in comparison with other pro-

kinetics, better normalizes the motility of the esophagus, smooth muscles of the stomach and the initial sections of the intestine. It is more effective in the treatment of patients with anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, especially in patients with diabetic gastropathy.

It is generally accepted that metoclopramide and domperiodon remain very effective and significant drugs in the treatment of gastric and intestinal dyskinesias in pediatric practice. Metoclopramide in such a situation is less convenient, because it sometimes causes drowsiness, asthenia.

Domperiodon is rapidly absorbed from the gastrointestinal tract. The maximum concentration in the blood is reached after one hour. Up to 90% of the drug binds to blood proteins. Poorly penetrates the blood-brain barrier. The half-life is 7-9 hours. 31% of domperidone metabolites are excreted in the urine; with feces - 66%. It is not recommended to prescribe the drug to persons with hypersensitivity to it, with gastrointestinal bleeding, intestinal obstruction, pregnancy. Sometimes the patient may experience headache, dizziness, dry mouth, stool retention, urticaria while taking the drug.

Cisapride. The drug excites serotonin receptors and thereby contributes to a more rapid release of acetylcholine from the cholinergic neurons of the mesenteric plexus. This leads to an increase in the sensitivity of m-cholinergic receptors of the smooth muscles of the gastrointestinal tract to it, which, in turn, stimulates the tone and motor activity of the esophagus, stomach and intestines, normalizes the activity of the sphincters of the gastrointestinal tract, and promotes propulsion of food from the stomach and chyme in the intestine.

Cisapride is rapidly absorbed from the intestine, reaching a maximum plasma concentration in 1.0-1.5 hours. Bioavailability is 35-40%. It binds to blood proteins, mainly albumin, by 97-98%. In the liver, it undergoes intense N-dealkylation with the participation of cytochrome P-450 isoenzyme 3A4 and turns into an inactive metabolite norcisapride. About 10% of the drug is excreted unchanged in urine and feces. Anticholinesterase drugs and m-cholinomimetics enhance the effect, cimetidine accelerates absorption. Ketoconazole, erythromycin, clarithromycin increase the concentration of cisapride in the blood, which increases the risk of developing arrhythmias.

Cisapride is most widely used in the treatment of patients with dyskinesias of the esophagus, stomach and intestines, caused by many causes, occurring both as a primary disease,

and secondary, for example, reflux esophagitis, non-ulcer dyspepsia, irritable bowel syndrome, etc.

When using cisapride, side effects such as dizziness, extrapyramidal disorders, convulsive muscle twitching, drowsiness, headache, episodic cardiac arrhythmias, nausea, vomiting, and a number of others may occur.

The following diseases are considered contraindications to the use of cisapride: hypersensitivity to the drug; acute diseases organs of the digestive system: gastrointestinal bleeding; intestinal obstruction; perforation of the stomach or intestines; pregnancy and breastfeeding period.

Cisapride has been shown to, in rare cases, prolong the Q-T on the electrocardiogram, against the background of which life-threatening rhythm disturbances (ventricular tachycardia "pirouette") may occur. It is believed that this effect of cisapride in the vast majority of cases is due to its irrational use: overdose of the drug, combination with drugs that inhibit the activity of the cytochrome P-450 isoenzyme CYP3A4 (macrolide antibiotics). Negative effects of cisapride may occur with low blood levels of calcium, potassium, magnesium; with deep violations of liver function; with congenital Q-T syndrome.

Caution is required when prescribing cisapride to premature infants within three months of birth.

20.10. MEDICINES USED IN INTESTINAL DYSBACTERIOSIS

Dysbacteriosis is a condition characterized by a violation of the mobile balance of the intestinal microflora with the appearance of significant amounts of microbes in the small intestine and a change in the microbial composition of the colon. The extreme degree of intestinal dysbacteriosis is the appearance of bacteria of the gastrointestinal tract in the blood (bacteremia) or even the development of sepsis.

By itself, dysbacteriosis is not an independent disease. It occurs when there is a violation of intestinal digestion, dyskinesia of the stomach and intestines, changes in local immunity, with the use of antibiotics and other drugs, with a number of diseases of the stomach and intestines, after surgical interventions, etc. Signs of dysbacteriosis in various combinations are found in almost all patients with chronic diseases intestines, with certain changes in nutrition and exposure to certain factors

environment. At its core, intestinal dysbacteriosis is a bacteriological concept, and not a nosological form.

In the treatment of patients with intestinal dysbacteriosis, a variety of drugs are used. These include the following drugs.

Antifungal drugs: tetracyclines, penicillins, cephalosporins, fluoroquinolones, metronidazole, intetrix *, ersefuril *, furazolidone; sulfa drugs (ftalazol *, sulgin *).

Antifungal drugs.

Bacterial preparations: bifidobacteria bifidum (bifidumbacterin *), bifiform *, acidophilic lactobacilli (lactobacterin *), bactisubtil *, linex *, enterol *, etc.

Products of microbial metabolism: hilak forte *.

Regulators of digestion and intestinal motility: enzymatic preparations and preparations containing bile components (panzinorm forte-N *, digestal *, festal *, enzistal *, etc.); carminative preparations; drugs that restore impaired propulsive function of the intestine (loperamide, trimebutine).

Immunomodulators: thymus extract (tactivin *, thymalin *), thymogen *, immunal *, etc.

Medicinal plants and preparations of natural origin.

Laxatives.

Antidiarrheals.

The characteristics and clinical and pharmacological features of these drugs are mainly described above. In more detail, we will focus on bacterial preparations and preparations of microbial metabolism used to normalize the intestinal microflora.

Baktisuptil*. One capsule contains at least 1 billion pure dry culture of the bacterium strain IP 5832 with vegetative spores. When entering the intestine, it contributes to the correction of the physiological balance of the microflora. The vegetative forms of the bacteria contained in the preparation release enzymes that break down carbohydrates, fats, proteins, and in the acidic environment created by them, they prevent the processes of decay. In addition, bactisuptil optimizes the synthesis of B and P vitamins in the intestine.

Bifidumbacterin*. Produced in bags of aluminum foil. One sachet contains 5x10 8 CFU of freeze-dried microbial cells of live bifidobacteria antagonistically active

strain Bifidobacterium bifidum N 1, purified from the cultivation medium, and 0.85 lactose-bifidogenic factor. Bifidumbacterin * in this case is an antagonist of most pathogenic and opportunistic microorganisms of the colon. In addition, the drug stimulates the process of digestion, increases the nonspecific resistance of the body. It is indicated in the treatment of patients with intestinal dysbacteriosis, which occurred during the use of antibiotics, hormones; during radiation and chemotherapy; in patients in the postoperative period; with irritable bowel syndrome and other diseases of the colon. In adults, 1-2 sachets are used 3 times a day; the contents are mixed with the liquid part of the food at room temperature.

Bifiform *. Capsules of the drug, which dissolve in the intestine, contain at least 10 7 bifidum bacteria, as well as 10 7 enterococci. The drug is used 1-2 capsules a day with meals.

Hilak forte*. 100 ml oral drops contain a germ-free aqueous substrate of bacterial metabolic products Escherichia coli DSM 4087, Streptococcus faecalis DSM 4086, lactobacillus acidophilus DSM 4149, Lactobacillus helveticus DSM 4149 and other necessary components. The drug normalizes the intestinal microflora, affects the synthesis of epithelial cells of the mucous membrane, normalizes the pH of the colon and water and electrolyte balance. It is used for intestinal dysbacteriosis caused by various reasons.

Linex. One capsule of the drug contains 1.2x10 7 lactic acid lyophilized bacteria. Lactic acid bacteria, which are part of the drug, produce lactic acid and, to a lesser extent, acetic and propylene. They participate in the resorption of monosaccharides, stabilize the membranes of intestinal epithelial cells, and regulate the absorption of electrolytes. Acidification of the intestinal lumen slows down the growth of pathogenic and conditionally pathogenic microorganisms. In general, during course treatment with Linex, the intestinal microflora is normalized. The adult dose is 2 capsules 3 times a day.

In the 70s. as a result of a successful directed search for histamine receptor antagonists based on the "weighting" of the histamine molecule, H2-blockers appeared and firmly established themselves on the pharmaceutical market, and tagamet (cimetidine) became a truly "gold standard" of antiulcer therapy. The popularity and safety of drugs that block H2-histamine receptors is evidenced by the experience and many years of use in many millions of people; in a number of countries OTC sale of tagamet and ranitidine is allowed.

A prerequisite for the creation of H2-histamine receptor blockers was the discovery of powerful secretogenic activity in histamine in relation to the acid secretion of the stomach.

Histamine (P-aminoethylimidazole) is a biogenic substance that is widely present in body tissues and has high biological activity. In small concentrations and doses, it causes capillary vasodilation, increases capillary permeability, has a positive ino- and chronotropic effect in the myocardium, lowers blood pressure by reducing total peripheral resistance, helps to contract bronchial smooth muscles, is a powerful stimulant of gastric secretion, and irritates sensitive nerve endings. and has a number of other effects. The role of endogenous histamine in the development of anaphylaxis and allergic reactions, the regulation of the secretory function of the stomach, and the activity of the central nervous system is known.

From the standpoint of receptor pharmacology, histamine is an endogenous ligand of specific receptors (histamine receptors), which has an affinity for them, the ability to "recognize" (affinity, affinity) and interact with histamine receptors, which is the initial link in the chain of biochemical and physiological response processes at the level of a cell, tissue etc.

The population of histamine receptors is heterogeneous and consists of at least 2 subtypes, called H (- and H2-histamine receptors. The separation of receptors is based on the pharmacological principle, i.e., the presence of specific agonists for each subtype (for example, p-histine, 2-methylhistamine - for H1-receptors, 4-methylhistamine, betazol or dimaprit - for H2-histamine receptors).In the framework of the topic under consideration, it is especially important that gastric secretory reactions under the action of exogenous or endogenous histamine are realized through H2-histamine receptors.

The creation of drugs that block histamine H2 receptors is one of the greatest achievements in pharmacology in recent decades. Developed in the late 30s. and in recent years antihistamines(on modern classification H1-histamine blockers), being effective antagonists of histaminergic allergic reactions, do not eliminate histamine-induced HCl secretion. English scientist J. Black et al. (1972) conducted targeted research on the development of H2 receptor blockers. Molecules similar to histamine, but devoid of its agonistic properties, have been constructed. Previous experience and screening based on a similar technique in a number of compounds similar in structure to adrenaline led to the discovery of β-adrenergic receptor blockers. (In 1977, for the creation of H2-blockers and P-blockers, J. Black was awarded the Nobel Prize.) New drugs effectively inhibited gastric secretion, but turned out to be either unsuitable for enteral administration (burimamide) or hemotoxic (methiamid). Of these, the first drug acceptable in terms of safety was cimetidine, which entered clinical practice in the 1970s. Currently found a wide practical use drugs of the 2nd and 3rd generations (ranitidine, famotidine).

Preparations of H2-histamine blockers. The general principle of the chemical structure of H2-histamine blockers is the same, and specific compounds differ from histamine by a "heavy" aromatic part or a change in aliphatic radicals.

Drugs such as cimetidine, oxmetidine contain an imidazole heterocycle as the basis of the molecule. Other substances are derivatives of furan (ranitidine), thiazole (famotidine, nizatidine, thiotidine) or more complex cyclic complexes (roxatidine).

H2-histamine blockers are less lipophilic than their counterparts that block H1 receptors, and therefore more difficult to penetrate into the central nervous system. Along with the creation of selective peripherally acting H2-histamine blockers, a search is underway for compounds that affect mainly the central histamine receptors. In particular, solentidine, a highly lipophilic H2 antagonist, is being tested today, which prevents the action of histamine in the CNS, but has little effect on gastric secretion.

To date, 3 generations of H2-blockers have been formed. In our country, cimetidine (tagamet, cynamet, histodil, etc.), ranitidine (zantac, ranisan, peptoran, etc.), famotidine (pepsidine, gaster, lecidil, kvamatel, gastrosidin), nizatidine (axid), roxatidin (roxane) are used . They differ not only in chemical structure, but also in activity (for example, equivalent daily dosages in the series cimetidine: ranitidine: famotidine - 1: 3.3: 10) and safety (the drugs of the latest generation have a higher selectivity of the effect and a lower frequency of side effects) .

Preparations of H2-histamine blockers are produced by various pharmaceutical companies under various commercial names:

Both enteral dosage forms (tablets, capsules, pulvuls) and injections are used. (Table 3.5 shows approximate equivalent daily doses of various H2-histamine receptor blockers.)

Approximate daily doses of H2-blockers in the treatment of peptic ulcer

Note. The average duration of the drug prescription during treatment is 4-6 weeks (duodenal ulcers) and 6-8 weeks (gastric ulcers), the duration of the prophylactic course is from 2-3 months to several years.

Pharmacokinetics.

When taken orally, H2-blockers have a relatively high bioavailability, the value of which is about 90% for nizatidine, and lower for other drugs due to first pass metabolism in the liver. (Indicative pharmacokinetic parameters of the most common H2-histamine blockers in the clinic are given in Table 3.6.)

Maximum concentrations are usually reached within 1-2 hours after ingestion. The value of the maximum concentration depends on the dose of the drug. For example, after taking famotidine at a dose of mg, the maximum concentration is 0.04-0.06 μg / ml, and at a dose of 40 mg - 0.075-0.1 μg / ml. There is a definite relationship between the severity of the effect and the dose of H2-histamine blocker. So, for example, at a concentration of cimetidine 6775 μg / ml, secretion is suppressed by 50%, and at a concentration of 3.9 μg / ml - by 90%. The levels of effective concentrations can be used to judge the activity of drugs. So, IC50, i.e., the concentration that reduces stimulated acid production by 50%, for famotidine is 0.013 μg / ml, which is almost 2 orders of magnitude lower than that of cimetidine. In various observations on organs, cells or in the whole organism, the activity of famotidine is estimated to be 6-20 times higher than the activity of ranitidine, and the activity of cimetidine - 24-150 times.

H2-histamine blockers undergo partial biotransformation in the liver and in a significant amount (50-60%), especially when administered intravenously, are excreted unchanged by the kidneys. Thus, H2-histamine blockers are characterized by mixed (renal and hepatic) clearance. IN

The drug can enter the primary urine not only with the filtrate, but also through the mechanism of active tubular secretion.

The latter circumstance is proved by the fact that the calculated values ​​of renal clearance exceed the value of the renal filtration rate. Therefore, in patients with impaired renal function, a correction in the regimen of taking drugs of this group is necessary (see below).

Indicators of clearance and elimination half-life characterize the kinetics of excretion of H2-histamine blockers from the body.

The main pharmacokinetic parameters of H2-histamine blockers

The elimination half-life of nizatidine is shorter (about 1.2 hours) than that of other drugs (2-3 hours). It should be noted that the duration of the effect is not equivalent to the half-life, since with increasing doses, the time to maintain plasma concentrations in the range exceeding the therapeutic one increases, and, accordingly, the duration of secretory depression increases. So, ranitidine and cimetidine have similar elimination parameters, but due to the fact that ranitidine is several times more active, it can be administered twice a day while maintaining the therapeutic concentration for 8-12 hours.

In patients with renal insufficiency (for some drugs (cimetidine) and with impaired liver function), as well as in elderly patients, the clearance of H2-histamine blockers is reduced. They are able to penetrate the blood-brain barrier. The ratio of concentrations in the cerebrospinal fluid and plasma is 0.05-0.09. In lactating women, H2-histamine blockers may pass into milk in quantities sufficient to have a pharmacological effect on the child. (Some factors affecting the pharmacokinetics of drugs in this group are summarized in the table)

Factors affecting the pharmacokinetics of H2-histamine blockers

Pharmacodynamics.

H2-histamine blockers - specific antagonists of H2-histamine receptors, i.e. substances that are able to "recognize" the corresponding receptors, but lack " internal activity"(i.e., they are not able to activate this receptor and initiate a specific physiological reaction). The effect of H2-histamine blockers is characterized by selectivity, i.e., the absence of antagonistic properties against H (-histamine receptors, muscarinic and nicotinic cholinergic receptors, a- and (b- In experiments on preparations of isolated organs, oxinth glands and isolated dispersed parietal cells, as well as in the study of the secretory function of the stomach in animals and humans, H2-blockers act as typical competitive antagonists, differing from each other in affinity characteristics (receptor affinity) , the kinetics of binding to the receptor and dissociation.These differences cause a significant range of fluctuations in activity indicators.For example, when comparing the effect of 3 common drugs in in vivo models, famotidine (its activity is taken as 1) is 7-20 times more active than ranitidine and in 40-150 times - cimetidine, and they are active st in experiments in vivo correlates as 1:24-124.

In accordance with the patterns of competitive antagonism, H2-histamine blockers act depressingly on the secretory reactions of parietal cells, depending on the dose.

Dose-dependence of the antisecretory effect of an antagonist of the H2 subtype of histamine receptors

Basal acid production, nocturnal secretion, HCl secretion stimulated by pentagastrin, H2-agonists, caffeine, insulin, false feeding, stretching of the fundus of the stomach are suppressed.

Pharmacodynamics of H2-histamine blockers

In high doses, these blockers suppress the secretory response almost completely. For example, nizatidine taken at night at doses of 30,100 and 300 mg suppresses nocturnal acid secretion by 53.67 and 90%, respectively; while the pH values ​​are 2.48-4.09-6.15 (Table 3.8). After taking amifentidine in doses of 10 and 20 mg, basal acid production is reduced by 8 and 98%, stimulated by 45 and 90%, and the pH increases to 3.2 and 7.3. Along with this, the acidity of gastric contents decreases, and the pH increases. With increasing doses, the duration of the secretory reaction increases (for example, the effect of famotidine at doses of 20.40 and 80 mg lasts 12.18 and 24 hours, respectively). Both the concentration of H + and the amount of gastric juice decrease. When taken repeatedly, the effect, as a rule, is reproduced and no pronounced tolerance is detected. However, it should be noted that acid production is not always suppressed by H2-histamine blockers. Categories of patients with gastroduodenal ulcers resistant to therapy with H2-histamine blockers were identified. There is evidence that in these cases there is a refractoriness to the antisecretory effect, especially evident in the night pH-metry. The contribution of vagotonia is discussed, as well as the possibility of participation of tachyphylaxis in the genesis of the phenomenon of refractoriness to the action of this group of drugs.

Recently, evidence has appeared that under the influence of H2-histamine blockers, the protective properties of the gastroduodenal mucosa also change. The course use of ranitidine, famotidine leads to an increase in the formation of prostaglandin E2 in the gastric and duodenal mucosa, through which a cytoprotective effect is realized (see below).

Depending on the dose of H2-histamine blockers, there is a decrease of 30-90% in pepsin production, but the secretion of bicarbonate and mucus changes little. However, there are reports of unequal effects of individual drugs on the quality of gastric mucus, in particular on the ratio of neutral mucoproteins to their total amount ("mucoprotective index"), which after a monthly course of administration may decrease (cimetidine, famotidine, but not ranitidine). This action is associated with individual pharmacological characteristics, for example, with concomitant cholinergic effects. Perhaps this feature of pharmacodynamics affects the frequency of relapses after treatment with the corresponding drug.

It is allowed that H2-histamine blockers have an anti-helicobacter effect. The possibility of an indirect effect on H. pylori is discussed, since the average environment is "uncomfortable" for the bacterium. A direct effect (ebrotidine) is not excluded.

Unlike anticholinergics, H2-histamine blockers do not have a significant effect on the motility of the gastroduodenal region, as well as on pancreatic secretion.

In response to a decrease in the acidity of gastric contents, an increase in the production of gastrin occurs, hypergastrinemia is noted.

There is evidence of an increase in the production of prostaglandin E2, which may play a role in accelerating the healing of ulcers in the treatment of H2-histamine blockers. Against the background of the block of H2-histamine blockers, the damaging effect (petechiae, microbleeding) of large doses of aspirin decreases.

H2-histamine receptors are also present in other organs and tissues, so there is also an extrasecretory (extragastric) effect of their blockers. Although histamine (due to the activation of cardiac H2-histamine receptors) is able to speed up and intensify heart contractions, its role in the normal physiology of the heart remains insufficiently elucidated. H2-histamine blockers have little effect on blood pressure, heart rate, ECG, although there are reports of a decrease in stroke and minute volumes. In any case, the cardiotropic effects of this group of drugs should be borne in mind as possible unwanted effects(see below).

In experiments on isolated bronchial muscles, blockade of H2-histamine receptors can enhance the bronchoconstrictor reaction in response to histamine or antigenic stimulus, however, in general, significant reactions of this nature are not observed in the body. Some blockers (for example, cimetidine) increase prolactin secretion, displace testosterone from its binding sites and increase the serum sex steroid concentration, reduce the weight of the testes and prostate, and also bind to cytochrome P-450-dependent enzymes that play an important role in the functioning hepatic systems for the oxidation of xenobiotics, in particular medicinal substances (see "Side Effects").

Indications for use.

The main indication for the use of H2-histamine blockers is ulcerative lesions of the gastroduodenal zone. With duodenal ulcers, the drugs have a clear symptomatic effect: pain decreases after 4-5 and disappears after 10-11 days, dyspeptic disorders (heartburn, belching, nausea, vomiting) are eliminated within a week. An indirect indicator of the relief of the symptoms of "acidism" is a decrease in the consumption of antacids. Within two weeks, local pain on palpation and percussion also decreases and disappears. (Indications for the use of this group of agents are summarized schematically in Table 3.10.)

There are numerous observations confirming the fact of accelerating the healing of ulcers in the treatment of H2-histamine blockers. On average, the frequency of healing over a 4-6-week period is approximately 2 times higher than that of placebo. Already after 4 weeks, the percentage of healing with endoscopic control of duodenal ulcers reaches 60-80%, and after 6-8 weeks it fluctuates within 70-90 and 90-100%, respectively. More slow dynamics in gastric ulcers.

The data of comparative studies of H2-histamine blockers do not allow making a categorical conclusion about significant differences in their effectiveness, which mainly come down to unequal values ​​of effective daily and course dosages of the Drugs used in practice. It should be noted that daytime or evening intake may have an unequal effect on the dynamics of nocturnal and daytime secretory reactions and pH levels. So, when taking roxatidine in doses of 75 mg 2 times a day or 150 mg at night, the average daytime pH values ​​were 3.8 and 2.4, respectively (initial value 1.6), and nighttime - 3.0 and 5.9 ( initial - 1.5). However, both regimens were clinically equally effective.

An important element of therapy with H2-histamine blockers is their use for maintenance and anti-relapse treatment. In the first case, it is fundamentally important to prevent abrupt withdrawal and secretory return, which contributes to a relapse. Anti-relapse treatment is based on long-term (up to several years) administration of H2-histamine blockers. Drugs are usually prescribed at night in reduced dosages (see table). The frequency of relapses, according to different authors, with maintenance admission is 2-3 times lower than with placebo.

The use of H2-histamine blockers

Indications for the use of H2-histamine blockers can serve not only peptic ulcer disease, but also conditions in which acidic gastric secretion plays the role of a leading pathogenetic factor or contributes to pathological changes: Zollinger-Ellison syndrome, reflux esophagitis, bleeding from the upper gastrointestinal tract, anastomositis, persistent gastritis and duodenitis, and other diseases accompanied by an increase in acidity with severe symptoms.

Much attention is paid to the possibilities of using H2-histamine blockers for the prevention of stress-induced mucosal damage. Erosive and ulcerative lesions of the mucosa are observed in 60-100% of patients in critical condition due to severe burns, multiple injuries, sepsis, brain injuries, renal failure; at the same time, gastrointestinal bleeding develops in 10-20% of cases. In recent years, in such patients, H2-histamine blockers have been successfully replacing antacids. The optimal way to administer H2-blockers in these situations is considered parenteral (drip or bolus), because it provides a stable increase in pH.

H2-histamine blockers have a preventive effect in gastropathy associated with the use of non-steroidal anti-inflammatory drugs. Along with antacids, metoclopramide (cerucal), H2-histamine blockers are successfully used in anesthesiology for general anesthesia, to prevent aspiration of acidic gastric contents and reduce the risk of developing aspiration pneumonia.

It should be noted that the dosage of drugs (single, daily and course) depends on the specific indication or on the purpose of their use - therapeutic or prophylactic (anti-relapse). The highest doses are prescribed for conservative therapy Zollinger-Ellison syndrome (for example, ranitidine - up to 6 g per day, famotidine - 20-40 mg 4 times a day or more often). With reflux esophagitis, the drug load is usually higher (in terms of dose and duration of treatment) than with peptic ulcer disease. For the prevention of Mendelssohn's syndrome, drugs are used orally or in injectable form the day before and before surgery.

Side effects.

Many years of experience in the use of H2-histamine blockers has shown that these are relatively low-toxic and safe drugs. Millions of patients have undergone course treatment without serious adverse effects. In short-term courses, sometimes (1-7% of cases) there are stool disorders (diarrhea, constipation), skin rash, headaches and muscle pain, dizziness, loss of appetite.

With prolonged blockade of H2-histamine receptors, adaptive reactions develop in the form of a change in the density of receptors or their affinity for histamine, therefore, abrupt withdrawal of the drug leads to secretory recoil (withdrawal syndrome, "rebound", etc.), which can provoke a relapse of the disease. Because of the foregoing, it is very important to follow a gradual change in dosage and pharmacological protection of other antisecretory agents when canceling H2-histamine blockers.

The experience of long-term use of cimetidine showed that in hepatocytes it is able to bind to enzymes containing cytochrome P-450, and thus inhibit the function of the microsomal oxidative system, as a result of which the first phase of biotransformation in the liver of drugs that interact with the hepatic microsomal system is disrupted. The interaction of these drugs at the level of hepatic oxidases may result in an increase in their effect.

Medications biotransformed by liver microsomal oxidases

A classic example illustrating this effect of cimetidine is its ability to reduce the clearance of antipyrine or amidopyrine, thereby increasing the serum concentration of the respective drugs. According to recent data, modern therapeutic doses and regimens can reduce the risk of drug interactions. An essential advantage of H2-histamine blockers of the 2nd-3rd generations (ranitidine, famotidine) is the absence or slight interaction with the hepatic system of drug biotransformation. In certain cases, interaction with cytochrome P-450-containing enzymes also finds useful application(prevention of hepatotoxicity of acetaminophen, halothane).

It is also noted that cimetidine reduces hepatic blood flow, and this contributes to the interaction with other drugs. Cases of an increase in the concentration of creatinine, serum urea, an increase in the activity of transaminases, and hyperbilirubinemia are described. Cimetidine can reduce the active secretion by the kidneys of certain drugs and their metabolites (for example, novocainamide and its acetylation product, N-acetyl novocainamide), which leads to an increase in their plasma concentration.

An example of another variant of the interaction of H2-histamine blockers is their ability to inhibit the metabolism of ethanol by the gastric mucosa, which causes an increase in the concentration of ethanol in the blood.

In patients with impaired renal function, the dosage of H2-histamine blockers is reduced, usually focusing on creatinine clearance (Table 3.12). The drugs pass through the placental barrier, can be excreted in breast milk, so they are not recommended during pregnancy and lactation.

Adjustment of doses of H2-histamine blockers in patients with renal insufficiency

Cimetidine binds to androgen receptors, is able to displace labeled testosterone in the experiment and has an antiandrogenic effect. With long-term administration in large doses, libido and potency disorders were observed. The drug can change the level of prolactin, cause gynecomastia. The antiandrogenic effect is not characteristic of new generations of H2-histamine blockers.

Penetrating through the blood-brain barrier, H2-histamine blockers sometimes cause disorientation, confusion, especially in the elderly.

In large doses, usually when administered intravenously, the drugs block atrial H2-histamine receptors and can provoke arrhythmias. It was noted above that myocardial histamine receptors are involved in the control of chronotropy (presumably H2 receptors), inotropy (both types of receptors) and metabolism (H2 receptors). At a plasma histamine concentration above 1 ng / ml, it exhibits the properties of an arrhythmogen. Against the background of the block of H2-histamine receptors, the level of histamine may increase, and its effect can be added to the arrhythmogenic properties of prolactin, the concentration of which also increases after taking blockers (cimetidine).

There are concerns that prolonged artificial change in the environment of the stomach predisposes to carcinogenesis. Pharmacogenic anacidity promotes bacterial proliferation (nitrosobacteria) and increases the level of nitrosamines, including due to nitrosation of the molecule of certain drugs (cimetidine) in the stomach. Nitrosamines, binding to DNA, provoke carcinogenesis. However, no convincing clinical and statistical evidence of this point of view has been obtained.

There are reports that cimetidine and famotidine also affect the absorption of certain drugs, in particular they interfere with the absorption of ketoconazole.

Cimetidine solutions are incompatible in one syringe with alkaline injection solutions (eufillin, dipyridamole, polymyxin B, penicillins, cephalosporins, etc.).

A list of some registered side effects of antisecretory drugs of this group without indicating their frequency is presented in the table.

Side effects of H2-histamine blockers

Summarizing the pharmacological characteristics of H2-histamine blockers, we note that individual preparations differ mainly in their pharmacokinetic characteristics and safety profile. Data on their clinical use indicate comparable efficacy for the treatment of peptic ulcer and the prevention of recurrence.

Prospects for the creation of new generations of H2-histamine blockers. In recent years, a new generation of H2-histamine blockers has been researched and studied, the action of which is not limited to the suppression of acid production. The most famous representative is ebrotidin). It is part of a new chemical family of H2-histamine blockers - pharmacomidins. The main feature of ebrotidine is a combination of antisecretory, gastroprotective and antihelicobacter properties.

As an antisecretory agent ebrotidine- a typical representative of H2-histamine blockers, having a high affinity for H2-histamine receptors. The clinical pharmacodynamics of its antisecretory action (at a daily dose of 400-800 mg in one dose) is comparable to that of ranitidine (at a daily dose of 300 mg). In some studies, however, there is a higher efficacy of ebrotidine. The drug causes a transient increase in the level of gastrin in the blood.

The antisecretory effect of ebrotidine, apparently, is not limited to its ability to block H2-histamine receptors. The increase in secretion in Helicobacter pylori infection is due, in particular, to the suppression of the regulatory inhibitory mechanism, the mediator of which is somatostatin. Lipopolysaccharides produced by H. pylori inhibit the binding of somatostatin to the corresponding receptor, while ebrotidine prevents this. In addition, ebrotidine is a non-competitive antagonist of carbonic anhydrase (isoenzyme forms I and II), which plays an important role in the mechanisms of secretion and, in particular, its activation under the action of ulcerogenic substances.

The pharmacokinetics of ebrotidine has been studied. When administered orally (150-800 mg), the maximum concentration (364-1168 ng / ml, depending on the dose) is reached after 2-3 hours. The elimination half-life is 9-14 hours. within 24-48 hours. 10-24% of the drug is excreted in the urine unchanged or in the form of sulfoxide.

Of great interest is the gastroprotective effect of ebrotidine. In the experiment, it is most clearly manifested in models of the damaging effect on the gastric mucosa of chemical agents (ethanol, ammonium, taurocholate, lipopolysaccharides), non-steroidal anti-inflammatory drugs (indomethacin, aspirin, piroxicam) and stress. Ebrotidine has the ability to prevent mucosal damage and accelerate the process of proliferation and healing. The gastroprotective potential of ebrotidine may even exceed that of sucralfate. The available data suggest that the protective effect of ebrotidine is associated with the activation of all the main components of protection, in particular preepithelial (alkali and mucus secretion), epithelial (surfactant phospholipids, mucosal restorative potential) and postepithelial (microcirculation), and not only with stimulation of prostaglandin mechanism in the stomach.

Effects proving the gastroprotective potential of ebrotidine:

1. Stimulation of mucus secretion and change in its quality. Changing the physicochemical properties of the gel, increasing its viscosity, hydrophobicity, and the ability to prevent the transit of H +. This is based on an increase in the synthesis and secretion of sulfo- and sialomucins and mucus phospholipids, and an improvement in their ability to form macromolecular ensembles. At the molecular level, there is an increase in the expression of the so-called. integrin receptors interacting with the protein of the extracellular matrix (laminin).

2. Improvement of the proliferative properties of the mucosa, which is indicated by an increase in the expression of growth factors, in particular EGF and PDGF.

3. Increased blood flow, which is considered as a consequence of an increase in the concentration of prostaglandin E2 and nitric oxide. The latter is proved, in particular, by the fact that inhibition of NO synthase reduces the effect of ebrotidine. The preservation of the effect of ebrotidine against the background of the action of indomethacin confirms that not only the prostaglandin mechanism is involved in this process.

4. Antihelicobacter action:

1) ebrotidine interacts with the surface receptors of epithelial cells and suppresses the urease, lipase, protease and mucolytic activity of Helicobacter pylori. H. pylori proteases are known to cause degradation of a number of epithelial growth factors, especially TGF-P and PDGF. The inhibitory effect of ebrotidine on the rate of degradation is higher than that of sucralfate;

2) ebrotidine prevents the damaging effect on the mucosa of substances-products of the activity of H. pylori, in particular lipopolysaccharides, which can disrupt the integrity of the epithelium and ammonium. The drug eliminates the violation of the binding of mucin to the epithelial receptor, which occurs under the influence of the products of the activity of H. pylori;

3) ebrotidine exhibits a direct anti-Helicobacter pylori action in vitro. For example, the inhibitory concentration of ebrotidine against H. pylori is 75 µg/ml, while ranitidine does not show such an effect at concentrations exceeding 1000 µg/ml. This effect is combined with the potentiation of the anti-helicobacter effect of antimicrobial agents. Thus, ebrotidine, unlike ranitidine, increases the activity of erythromycin and amoxicillin by 3 times, clarithromycin by 5 times, and metronidazole by 9 times.

5. Ebrotidine reduces DNA defragmentation and programmed cell death (apoptosis) in the gastric mucosa when exposed to non-steroidal anti-inflammatory drugs (indomethacin). Apoptosis is associated with increased production of tumor necrosis factor, TNF-α, and ebrotidine (less active sucralfate, ineffective omeprazole) prevents both cytokine production and apoptosis.

Other interesting aspects of the action of ebrotidine have also been found. In clinical trials, particularly in double-blind, multicentre trial settings, ebrotidine (400-800 mg daily in single doses at night) has been shown to be extremely effective drug in the treatment of gastroduodenal ulcers. Compared with ranitidine, it has (according to several studies) a markedly greater efficacy, especially in patients who smoke. The safety profile of the drug is highly rated. Ebrotidine is considered in the future as the drug of choice in the treatment of gastric diseases associated with H. pylori infection.