Catad_tema Clinical pharmacology - articles

Catad_tema Peptic ulcer disease - articles

Non-steroidal gastropathy: modern methods of prevention and treatment

Published in the magazine:
"Lectures for doctors"; Gastroenterology; No. 3; 2011; pp. 10-16.

PhD A.F. logins
Institute for Advanced Training of Physicians of the Federal State Institution “National Medical and Surgical Center named after N.N. N.I. Pirogov" Ministry of Health and Social Development of Russia

The term "drug gastropathy", used in the lexicon of modern medicine, is a collective concept that includes dyspeptic syndrome, as well as erosive and ulcerative lesions of the upper gastrointestinal tract (GIT), which develop when taking drugs that have irritating and damaging action on the mucous membranes (CO) of the stomach and, less often, the duodenum.

In general terms, changes when taking such medications can be defined as chemical gastritis (according to the Sydney classification), but morphological changes in CO, ulceration and erosion, determined by light microscopy of biopsy material, cannot be strictly characterized as chemical. Inflammatory changes in the gastric mucosa are detected in almost 100% of cases in patients taking medications with an ulcerogenic effect, and differ only in the severity and frequency of development of erosive and ulcerative defects of the mucous membrane.

The most widely used group of drugs that have a damaging effect on the mucous membrane of the upper gastrointestinal tract are non-steroidal anti-inflammatory drugs (NSAIDs). The emergence of the term "NSAID-gastropathy" is associated with the identification of changes in the structure of the gastric mucosa caused by taking NSAIDs.

The second significant factor that must be taken into account by specialists using NSAIDs in medical practice is the high frequency of life-threatening complications that develop against the background of erosive and ulcerative lesions of the mucous membrane, primarily bleeding.

The relevance of the problem of prevention and treatment of NSAID-gastropathy is beyond doubt. The group of non-steroidal anti-inflammatory drugs is extremely widely in demand in rheumatology, cardiology clinics, for the treatment of pain and non-specific inflammatory processes. In the last decade, the appointment of NSAIDs to reduce the risk of developing cancer in patients with precancerous processes in the colorectal region, both genetically determined and arising against the background of diseases in this area, has been actively discussed. From year to year, the indications for prescription are expanding, the number of drugs from the NSAID group that block the "inflammatory" enzyme - cyclic oxygenase type 2 (COX-2) is increasing.

Thus, the prevention and proper treatment of gastroenterological side effects and complications associated with the use of NSAIDs are of great practical importance for specialists in various fields.

Mechanisms of development of NSAID-gastropathy

Inhibition of the production of the enzyme cyclooxygenase (prostaglandin synthetase). COX is an enzyme that catalyzes the synthesis in the body of biologically active substances - prostanoids, the most important of which are prostaglandins, thromboxane and prostacyclin. A group of prostanoids performs the functions of mediators of pain, the implementation of tissue inflammation, and the regulation of adequate platelet lacing. For the gastrointestinal tract, the most important is the functional activity of one of the COX isoenzymes, cyclic oxygenase type 1 (COX-1), physiological, normally constantly present in the tissues of a living organism and ensuring the regulation of the functions described above. The COX-2 isoform is not detected in normal tissues. The expression of COX-2 is induced by inflammatory mediators (lipopolysaccharides, interleukin-1, tumor necrosis factor alpha) from the cellular substances of the body (macrophages, monocytes, vascular endothelial cells, etc.) and causes all clinical manifestations of inflammatory processes - pain, fever , swelling, dysfunction of the organ.

direct toxic effect. According to the molecular structure, most NSAIDs are weak acids. When taken orally in the gastric contents, they are easily ionized, diffuse into the cells of the gastric mucosa and, upon reaching a certain concentration in epitheliocytes, have a direct damaging effect on intracellular organelles and destroy epitheliocytes.

Systemic toxic effect. NSAIDs, regardless of the form of application (oral, injection, rectal, local) enter the systemic circulation and inhibit the production of mucins, impair microcirculation in the CO, reducing its trophic and reparative properties and thereby reducing the proliferation of epithelial cells of the gastric mucosa, and therefore reducing the protective factors of the mucosa shells.

The leading role in the development of NSAID-gastropathy is given to the inhibition of COX-1 by reducing the synthesis of protective (cytoprotective) prostaglandins PGE1 and PGE2, which regulate the synthesis of mucins, regional blood flow and secretion of bicarbonates. The "ancestor" of NSAIDs is rightfully considered acetylsalicylic acid (ASA). The popularity and demand for this drug is best evidenced by the numbers: in the 70s of the XX century in the UK, almost 2 thousand tons of ASA were consumed annually (an average of 2 tablets per week for each inhabitant). Back in the early 1990s, in domestic and Western guidelines on rheumatology, ASA was recommended as a first-line drug for analgesic and anti-inflammatory therapy for articular pathology at an initial daily dose of 3-4 g / day.

The attitude to ASA drugs, due to the increase in the number of side effects, reflects the famous statement of D. Lawrence and P. Benitt: “... if at present it was necessary to administer acetylsalicylic acid, it is unlikely that any of the responsible persons would have the courage to allow its sale population."

According to A.E. Karateeva, “... in the hands of an experienced therapist, NSAIDs are a reliable and convenient tool that allows you to quickly alleviate the patient's suffering and improve his quality of life. However, like any tool, these drugs are effective and safe only if they are used correctly. On the contrary, the inept use of NSAIDs without taking into account their pharmacological properties and the individual characteristics of the patient often results not only in disappointment in their effectiveness, but also in the development of dangerous, life-threatening complications. That is why the tactics of correct prescription, dose selection and determination of the duration of administration, control of not only the direct effect, but also possible adverse reactions and complications of NSAIDs, and, if they develop, timely and adequate treatment is the key to success in working with the patient.

Prevention of NSAID gastropathy

Prevention of the negative effect of NSAIDs on the GI tract is currently given a leading place in the treatment of diseases that require the appointment of non-steroidal anti-inflammatory therapy.

The most difficult measures, which at the same time provide a good result in reducing the number of side effects, are the refusal to use NSAIDs, minimizing the daily dose of the drug while maintaining an adequate anti-inflammatory and analgesic effect, as well as replacing NSAIDs with a drug of another group, with no damaging effect on the GIT. . Unfortunately, such measures may not be used in all clinical cases.

An effective measure for the prevention of complications is the choice of NSAIDs that are safer in relation to the mucous membranes of the upper gastrointestinal tract.

So, when taking drugs that equally block COX-1 and COX-2 (non-selective NSAIDs), such as piroxicam and indomethacin, gastropathy develops significantly more often than when using selective drugs that block inflammatory COX-2 to a greater extent and in less "physiological" COX-1, such as voltaren and ibuprofen, meloxicam.

Increasing the dose of selective NSAIDs, unfortunately, makes the risk of NSAID gastropathy equal to that with the use of a non-selective group of drugs. Thus, according to a meta-analysis by D. Henry et al. , the lowest risk of complications (gastrointestinal bleeding and perforation) was found with the use of ibuprofen at low doses, high doses of ibuprofen were associated with the same risk of complications as with non-selective NSAIDs. In a meta-analysis by S.C. Lewis et al. the lowest risk of gastrointestinal bleeding was obtained for ibuprofen (odds ratio (OR) 1.7; 95% confidence interval 1.1-2.5), for diclofenac the OR was 4.9 (3.3-7.1), for indomethacin - 6.0 (3.6-10.0), for naproxen - 9.1 (6.0-13.7), for piroxicam - 13.1 (7.9-21.8) and for ketoprofen - 34.9 (12.7-96.5).

There are also a number of additional factors that increase the risk of developing NSAID-gastropathy and more significant complications (erosions and stomach ulcers, bleeding). These include:

age over 65;

peptic ulcer in history;

large doses and / or simultaneous administration of several NSAIDs;

simultaneous reception of anticoagulants;

concomitant therapy with glucocorticosteroids;

duration of NSAID therapy;

the presence of a disease requiring long-term use of NSAIDs;

female;

smoking;

alcohol intake;

the presence of Helicobacter pylori infection.

The maximum risk of bleeding, regardless of the NSAID taken, occurs in the first week of admission (OR 11.7; 6.5-21.0), decreases with continued use of NSAIDs (5.6; 4.6-7.0) and becomes minimal one week after cancellation (3.2; 2.1-5.1).

The use of cytoprotective drugs that enhance the protective properties of the gastrointestinal mucosa against damage to NSAIDs is ineffective both for stopping the manifestations of dyspepsia and for reducing the number of side effects of NSAIDs in patients at risk, therefore, at present, the need to prescribe cytoprotectors (misoprostol, etc.) when using NSAIDs are not recognized by all researchers and are rarely used in practice.

Issues of drug prevention of side effects and complications when taking NSAIDs are discussed at international forums of specialists. To date, the most effective method is recognized as the simultaneous administration of NSAIDs and cytoprotectors or, more effectively, agents that reduce the acid-producing activity of the stomach (antisecretory drugs).

The use of effective drugs that reduce the production of acid ions and, accordingly, reduce the degree of acid aggression, primarily proton pump inhibitors (PPIs), can significantly reduce the risk of bleeding in the gastrointestinal tract, the development and recurrence of ulcers of the upper gastrointestinal tract, and also reduces the severity of dyspepsia. At the same time, according to A.E. Karateev, the combination of a selective NSAID and PPI is safer than the combination of a non-selective NSAID and PPI. This is confirmed by the results of similarly designed 6-month randomized controlled trials VENUS and PLUTO (n = 1378). According to the results obtained, in patients receiving PPIs at a dose of 20 and 40 mg, while taking non-selective NSAIDs, the appearance of ulcers was noted in 7 and 5% of patients, respectively, while in those receiving selective NSAIDs - only 1 and 4% (p< 0,05) .

Confirmation of the need for prophylactic administration of acid production inhibitors simultaneously with NSAIDs was also found in the results of the Phase II studies of OMNIUM and ASTRONAUT. Omeprazole at a daily dose of 20 mg was more effective for the secondary prevention of erosive and ulcerative lesions of the upper gastrointestinal tract than misoprostol 400 mg and ranitidine 300 mg. The criteria for effectiveness were: the absence of an ulcer, less than 5 erosions of the gastroduodenal mucosa, moderately severe dyspepsia. PPIs or misoprostol, as well as H. pylori eradication, may be considered as primary prevention options. The postulate that the eradication of H. pylori, if carried out before the start of a course of NSAIDs, reduces the incidence of ulceration, is included in the provisions of the Third Maastricht Consensus.

Treatment of erosive and ulcerative lesions caused by NSAIDs

The first of the most significant international consensus on the use of NSAIDs based on evidence-based medicine took place on the island of Sardinia in 2001. are the drugs of choice for healing ulcers caused by NSAIDs, especially gastric ulcers.

This conclusion is based on the results of several clinical studies, primarily OMNIUM (comparison of the effectiveness of omeprazole and misoprostol in the treatment of ulcers caused by NSAIDs) and ASTRONAUT (comparison of the effectiveness of omeprazole and ranitidine). These studies were carried out according to the same design in two phases: treatment - with the determination of effectiveness at the 4th, 8th and 16th weeks, and the secondary prevention phase (6 months). The studies included patients taking chronic NSAIDs (with rheumatoid arthritis or osteoarthritis), with endoscopically confirmed gastric ulcer, duodenal ulcer and/or erosions (at least 10 erosions of the gastroduodenal mucosa).

The results of the effectiveness of omeprazole in the healing of erosive and ulcerative lesions of the stomach and duodenum (duodenal ulcer) caused by NSAIDs, compared with misoprostol, are presented in table 1.

Table 1.

Healing of NSAID-induced erosive and ulcerative lesions of the stomach and duodenum after 8 weeks of treatment, according to the OMNIUM and ASTRONAUT studies

Omeprazole (at a dose of 20 mg) was found to be significantly more effective in scarring gastric ulcers than misoprostol (p = 0.004). It showed the greatest advantage in scarring of duodenal ulcers (p< 0,001). Интересно отметить, что при заживлении гастродуоденальных эрозий более выраженное действие оказывал синтетический аналог простагландина мизопростол (р = 0,01). Вместе с тем при его применении у 11% больных была выявлена диарея, 8,9% пациентов жаловались на абдоминальную боль, 16,9% преждевременно завершили прием препарата. Омепразол в дозах 20 мг и 40 мг оказался более эффективным по сравнению с ранитидином в заживлении всех указанных поражений.

In these studies, the first of the modern drugs of the group of antisecretory agents - proton pump inhibitors - omeprazole was used. To date, doctors have at their disposal other representatives of this class of acid production inhibitors (lansoprazole, pantoprazole, esomeprazole, rabeprazole). The action of this group of drugs is based on the mechanism of blocking the transmembrane transfer of protons, carried out by a specific enzyme - H + /K + -dependent ATPase or "proton pump". Reliable inhibition of the entry of hydrogen ions into the lumen of the stomach provides a double effect: conditions are created for adequate CO reparation by reducing the aggressive properties of gastric contents, and changing the pH of gastric juice to pH 5-6 reduces the activation of pepsinogen into pepsin to 20-30% of the initial values, which reduces the proteolytic properties of gastric juice, and therefore reduces the risk of autolysis of a blood clot (thrombus), which reduces the risk of recurrent bleeding due to the lysis of a thrombus formed in a bleeding vessel.

The peculiarity of all PPIs is that the active form of these compounds - sulfenamide, which is a cation, does not pass through cell membranes, remains inside the tubules and does not have side effects. The rate of activation and efficiency of PPI use depend on the pH of the medium and the value of the dissociation constant (pKa) for each drug. The optimum pH for all PPIs is between 1.0 and 2.0.

PPIs are the most powerful blockers of gastric secretion today. They inhibit the production of acid by almost 100%, and due to the almost complete irreversibility of fixation with the enzyme, the effect persists for several days, and the restoration of acid production occurs after 4-5 days, and therefore the rebound phenomenon is not typical for them.

PPIs, especially the latest generation drugs, selectively bind to two cysteine ​​molecules of the proton channel and have a stronger effect on H + /K + -ATPase, almost without affecting cytochrome P450 and without interacting with other drugs, which allows them to be used in various therapeutic combinations.

Pantoprazole Controloc at a daily dose of 40 mg is a safe and highly effective drug of choice for the prevention and treatment of gastropathy and erosive and ulcerative changes caused by non-steroidal anti-inflammatory drugs, including in elderly patients with comorbidities requiring medical treatment.

The use of modern PPIs is rarely accompanied by side effects. At the same time, with their long-term use, moderate hypergastrinemia develops with a slight increase in the number of enterochromaffin-like (ECL) cells, which is due to the reaction of G-cells of the CO from the stomach and duodenum in response to an increase in pH in the antrum of the stomach.

Clinical features of NSAID-gastropathy: a clinical picture with a minimum number of complaints, more often of a dyspeptic nature, lack of expression or complete absence of a signal pain syndrome due to the analgesic effect of NSAIDs; the presence of a drug load associated with the treatment of the underlying disease (NSAIDs or NSAIDs in combination with drugs of other groups) force the doctor to more carefully choose both preventive and therapeutic agents in the event of dyspepsia or erosive and ulcerative lesions of the gastrointestinal tract. Taking into account recent research, all these requirements are met by proton pump inhibitors. Considering the high efficiency of PPIs in acid-dependent diseases, the physician should opt for one of the types of H + /K + -ATPase inhibitors. The decisive factor of choice is not the rate of blocking the transmembrane transport of hydrogen ions and early relief of pain (as a rule, it is not pronounced or absent), but gradual and long-term and intense inhibition of acid production.

Of the proton pump inhibitors on the market, pantoprazole (Controloc) has the listed qualities, the bioavailability of which is 77%, plasma protein binding is 98%, and the maximum plasma concentration of the drug is reached 2-4 hours after administration. Food intake, as well as the route of administration of the drug (oral or intravenous) do not affect its pharmacokinetics. Compared to other PPIs, Controloc has little effect on the activity of the cytochrome P450 system, which clearly reduces its effect on the metabolic elimination of concomitantly taken drugs compared to omeprazole or lansoprazole. In the treatment of erosive and ulcerative lesions while taking NSAIDs, pantoprazole is recommended to be used at a dose of 40 mg / day, and more effective suppression of gastric secretion occurs when taking the drug in the morning. The use of pantoprazole is also indicated for the purpose of long-term maintenance prevention of ulcerative lesions of the upper gastrointestinal tract. According to H. Heinze et al. , the use of pantoprazole for the treatment of patients with peptic ulcer for 10 years or more was not accompanied by relapses of the disease and significant side effects, which fully complies with the requirements for a drug for the prevention and treatment of NSAID-gastropathy.

With prolonged use of Controloc, an increase in the concentration of gastrin in the blood occurs. According to some authors, a year after treatment, the content of gastrin increases on average 3 times, according to others - 2 times, the plateau is reached by the 9th month of taking the drug. The content of ECL cells during the year of treatment increases slightly - from 0.19 to 0.24%. These data suggest that pantoprazole Controloc is as safe as other PPIs.

At the same time, Controloc, unlike omeprazole and esomeprazole, does not accumulate in the body after taking repeated doses. Linear pharmacokinetics ensures the effectiveness of the drug throughout the course of treatment, starting from the first day of its administration. Pharmacokinetic parameters (AUC - 5.35 mg x h / l, maximum plasma concentration - 5.26 mg / l, half-life - 1.11 h) after intravenous administration of Controloc at a dose of 30 mg / day for 5 days were comparable to those obtained after its single intravenous administration.

Thus, it can be argued that pantoprazole Controloc at a daily dose of 40 mg is a safe and highly effective drug of choice for the prevention and treatment of gastropathy and erosive and ulcerative changes caused by the use of non-steroidal anti-inflammatory drugs, including in elderly patients with concomitant diseases requiring medication. treatment.

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... the presence of a combination of unique properties in non-steroidal anti-inflammatory drugs (NSAIDs): analgesic, anti-inflammatory, antipyretic and antiplatelet causes their extremely wide use in all areas of medicine.

… NSAIDs have a special place as the most commonly used and leading in the frequency of side effects.

… more than 30 million people in the world daily take NSAIDs, of which in 2/3 of cases this class of drugs is taken without a doctor's prescription and supervision.

... the medical and social significance of the problem is such that rheumatologists often call NSAID gastropathy "the second rheumatic disease."

________________________________________________________

NSAID gastropathy(NSAID-gastropathy; term proposed in 1986 by S. H. Roth)- these are erosive and ulcerative lesions of the gastroduodenal zone associated with the use of non-steroidal anti-inflammatory drugs and having a characteristic clinical and endoscopic picture.

Clinical manifestations of NSAID-gastropathy presented with the following symptoms: nausea, sometimes vomiting, a feeling of heaviness and pain in the epigastrium, bloating, anorexia and other dyspeptic disorders.

Approx. 50% patients suffering from NSAID-gastropathy, the disease can proceed with virtually no symptoms. Such life-threatening conditions as ulcerative-erosive lesions of the gastric mucosa and duodenum, bleeding can be the first and only sign of pathological changes in the gastrointestinal tract, which is especially important in elderly patients. Moreover, due to the peculiarities of antiprostaglandin activity, non-steroidal anti-inflammatory drugs quite often can "mask" the symptoms of the pathology of the gastrointestinal tract, thereby complicating the diagnosis and treatment of the disease.

To understand the pathogenesis of NSAID gastropathy, it is necessary to first consider the mechanism of action of NSAIDs.. The mechanism of action of NSAIDs is the same for all subgroups of drugs and is based on the inhibition of the cyclooxygenase (COX) enzyme, which plays a key role in the synthesis of arachidonic acid metabolites - prostaglandins, which have a pro-inflammatory effect and are directly involved in thermoregulation and the formation of pain sensations. By inhibiting this enzyme, NSAIDs reduce the manifestations of inflammation. There are two isoforms of COX, COX-1 and COX-2. COX-1 regulates the synthesis of prostaglandins, which provide the physiological activity of gastric mucus, platelets, and renal epithelium. COX-2 is involved in the production of prostaglandins in the area of ​​inflammation.

One of the most reasonable points of view on the pathogenesis of NSAID-gastropathy is that these specific complications of therapy are due to non-selective suppression of prostaglandin synthesis.

The pathogenesis of NSAID-gastropathy is based on two concepts:
(1) the concept of the local damaging effect of NSAIDs: being derivatives of weak organic acids, most NSAIDs in the acidic environment of the stomach are not ionized and penetrate through hydrophobic membranes into the cytosol of epitheliocytes, causing erosions and even shallow ulcers, mainly in the upper sections of the stomach (this mechanism of gastropathy induction is especially relevant during the first few days of NSAIDs- therapy);
(2) cyclooxygenase concept (non-selective inhibition of prostaglandin synthesis): by inhibiting the constitutional isoform of COX-1, NSAIDs cause a deficiency of prostaglandin І2, which leads to a deterioration in blood flow in the stomach wall; a decrease in the synthesis of prostaglandin E2 leads to a decrease in the secretion of bicarbonates and mucus, to an increase in acid production, which increases the imbalance of defense and aggression factors, promotes ulcerogenesis (this mechanism has a delayed development).

Considering the foregoing, it becomes clear that even reducing the dose of NSAIDs, switching to the rectal or parenteral route of administration of NSAIDs, as well as the use of drugs that protect the gastrointestinal mucosa, does not solve the problem of the risk of NSAID gastroduodenopathy, since this is the result of not a local, but a systemic reaction of the body.

Explanation to paragraph (2)> There are at least two cyclooxygenase isoenzymes that are inhibited by NSAIDs. The first isoenzyme - COX-1 - controls the production of prostaglandins (PG), which regulate the integrity of the gastrointestinal mucosa, platelet function and renal blood flow, and the second isoenzyme - COX-2 - is involved in the synthesis of PG during inflammation. Moreover, COX-2 is absent under normal conditions, but is formed under the influence of some tissue factors that initiate an inflammatory reaction (cytokines and others). In this regard, it is assumed that the anti-inflammatory effect of NSAIDs is due to inhibition of COX-2, and their undesirable reactions - inhibition of COX-1. The ratio of the activity of NSAIDs in terms of blocking COX-1 / COX-2 makes it possible to judge their potential toxicity. The smaller this value, the more selective the drug in relation to COX-2 and, thus, less toxic. For example, it is 0.33 for meloxicam, 2.2 for diclofenac, 15 for tenoxicam, 33 for piroxicam, and 107 for indomethacin. components of cell membranes and lysosomes, inhibition of the synthesis of surface-active phospholipids and cAMP, through the activation of neutrophils. These processes occur in all parts of the gastroduodenal zone, but are most pronounced in the antrum of the stomach, where there is a higher density of prostaglandin receptors, so the antrum is the favorite localization of NSAID gastropathy.

Criteria for the diagnosis of NSAID-gastropathy (Research Institute of Rheumatology, Moscow, V. A. Nasonova together with colleagues, 1991):
the appearance on the background of the use of NSAIDs of acute, usually multiple gastroduodenal erosions and / or ulcers with predominant localization in the antrum of the stomach;
lack of local inflammation and histological signs of gastritis;
oligosymptomatic or asymptomatic course and frequent manifestation of complications;
the tendency of ulcers to heal with the abolition of NSAIDs.

Risk factors for NSAID gastropathy:
established risk factors:
elderly age;
gastroduodenal ulcers or gastrointestinal bleeding, other gastroenterological diseases in history;
concomitant diseases and syndromes (arterial hypertension, cardiac, hepatic, renal failure) and their treatment (angiotensin-converting enzyme inhibitors, diuretics);
co-administration of anticoagulants, glucocorticoids or other NSAIDs with NSAIDs (except for low doses of acetylsalicylic acid);
taking high doses of NSAIDs;
the duration of NSAID therapy is less than 3 months;
the use of NSAIDs with a long half-life and COX-2 non-selective.
possible risk factors:
the presence of rheumatoid arthritis;
female;
smoking;
alcohol consumption;
Helicobacter pylori infection (debatable).

It is believed that NSAIDs do not affect the degree of H. pylori seeding of the mucous membrane of the gastroduodenal zone, the activity and the degree of inflammation in H. pylori-induced gastritis, but can exacerbate peptic ulcer disease. All NSAIDs (regardless of COX selectivity) delay the healing of peptic ulcers.

Degrees of risk of developing NSAID-gastropathy:
low risk of developing NSAID gastropathy - patients without a single established risk factor have it (traditional non-selective NSAIDs are allowed);
moderate risk of developing NSAID-gastropathy - patients with at least one identified risk fact (COX-2 inhibitor should be preferred);
high risk of developing NSAID gastropathy - have patients with two risk factors.

The risk of gastrointestinal bleeding is quite high with both targeted short-term and long-term use of NSAIDs. At the same time, there is every reason to believe that it is the duration of administration that is most responsible for the main danger of even over-the-counter NSAIDs.

Algorithm for the treatment of NSAID-gastropathy:
resolve the issue of the possibility of canceling NSAIDs;
if possible, then proton pump inhibitors (PPIs) in standard doses or histamine H2 receptor blockers should be prescribed;
if it is impossible to cancel NSAIDs, prescribe PPI;
treatment lasts from 4 to 8 weeks and is combined with H. pylori eradication as indicated.

Early subcardial erosions usually do not require discontinuation of drugs. In the case of detection of ulcerative lesions at any stage of NSAID therapy, the most rational is the abolition of NSAIDs or a COX-2 inhibitor and the appointment of a PPI (omeprazole, lansoprazole) in a standard dose (in the future - misoprostol). The same funds are used in the case when it is not possible to stop taking NSAIDs. In the treatment of NSAID-induced dyspepsia (in the absence of gastropathy), it is allowed to prescribe PPI at a standard dose (but not misoprostol, since in the first two weeks it often causes abdominal pain, diarrhea, in such cases its single dose of 200 mcg is halved; and the occurrence of metrorrhagia in postmenopausal women forced to stop the drug).

Prevention of NSAID-gastropathy

Prevention of early NSAID-gastropathy: the use of NSAIDs in rectal suppositories, injections and enteric tablets, topical NSAID therapy (applications of ointments, creams, gels on affected joints, etc.).

Prevention of NSAID-gastropathy according to large-scale controlled studies:
choice of COX-2 inhibitors;
or the choice of minimally toxic traditional NSAIDs (ibuprofen, diclofenac) in low doses;
the use of a combination of traditional NSAIDs with a synthetic analogue of prostaglandins (misoprostol);
or using a combination of traditional NSAIDs with any PPI at a standard dose.

With the appearance or aggravation of heartburn, pain in the epigastric region, nausea, patients taking NSAIDs, endoscopy is indicated to resolve the issue of further patient management tactics, the possibility of further NSAID therapy. It should also be taken into account that there is no correspondence between the clinical manifestations of NSAID gastropathy and endoscopic findings, therefore endoscopic control, especially in the early stages of treatment (the first 1–2 months), is a mandatory and adequate method for preventing severe complications.

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NSAID-induced gastropathy

RCHD (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical Protocols of the Ministry of Health of the Republic of Kazakhstan - 2018

Analgesic, antipyretic and anti-inflammatory drugs, unspecified (Y45.9), Dyspepsia (K30), Other analgesic, antipyretic and anti-inflammatory drugs (Y45.8), Other diseases of the stomach and duodenum (K31), Other non-steroidal anti-inflammatory drugs (Y45.3 ), Gastrointestinal bleeding, unspecified (K92.2), Peptic ulcer, site unspecified (K27), 4-Aminophenol derivatives (Y45.5), Propionic acid derivatives (Y45.2), Salicylates (Y45.1), Duodenal ulcer (K26), Gastric ulcer (K25)

Gastroenterology

general information

Short description

Approved
Joint Commission on the quality of medical services
Ministry of Health of the Republic of Kazakhstan
dated April 19, 2019
Protocol #63

NSAID-IGP- these are erosive and ulcerative lesions (EJP) of the GDZ mucosa, arising in chronological connection with the use of NSAIDs and / or acetylsalicylic acid (ASA) preparations.

INTRODUCTION

Protocol name: Gastropathy induced by non-steroidal anti-inflammatory drugs

ICD-10 code(s):
Gastropathy induced by the use of non-steroidal anti-inflammatory drugs - (NSAID-IGP) are absent in the International Classification of Diseases of the 10th revision (ICD-10).
Drugs (drugs) that cause damage to the mucous membrane (SM) of the gastroduodenal zone (GDZ) are presented in Table 1.

Table 1. Drugs that negatively affect GDZ according to ICD 10

Y45	Analgesic, antipyretic and anti-inflammatory drugs
Y45.1	Salicylates.
Y45.2	Derivatives of propionic acid.
Y45.3	Other non-steroidal anti-inflammatory drugs.
Y45.5	Antirheumatic agents.
Y45.8	Other analgesics, antipyretics and anti-inflammatory drugs.
Y45.9	Analgesic, antipyretic and anti-inflammatory drugs, unspecified.

Table 2. Diseases of the digestive system (ICD 10)

Combining the codes of these drugs and GDZ diseases according to ICD-10 (Table 2), we can formulate the diagnosis of NSAID-IHP.
Diagnosis examples:

• "NSAID-gastropathy: gastric ulcer (GU), complicated by bleeding" (Y 45.8, K 25, K 92.2);
• "NSAID-gastropathy: duodenal ulcer (DU) associated with the intake of acetylsalicylic acid (ASA), dyspepsia" (Y45.1, K26, K30)

Protocol development date: 2018

Abbreviations used in the protocol:

AAT	antiplatelet therapy
AG	arterial hypertension
ASC	acetylsalicylic acid
BN 2 RG	histamine H2 receptor blockers
BUT	rapid urease test
BHA	biochemical analysis
GDZ	gastroduodenal zone
DPK	duodenum
JCC	gastrointestinal bleeding
gastrointestinal tract	gastrointestinal tract
ischemic heart disease	cardiac ischemia
IPP	proton pump inhibitors
LS	medicine
NSAIDs	non-steroidal anti-inflammatory drugs
NSAID-IGP	NSAID-induced gastropathy
UAC	general blood analysis
OBP	abdominal organs
SO	mucous membrane
SO WPC	duodenal mucosa
coolant	mucous membrane of the stomach
ultrasound	ultrasonography
EGDS	zophagogastroduodenoscopy
I WOULD	peptic ulcer
YADPC	duodenal ulcer
IL	stomach ulcer
H. pylori	Helicobacter pylori

Protocol Users: gastroenterologists, internists, general practitioners (GPs), cardiologists, rheumatologists, neurologists.

Evidence level scale:

A	High-quality meta-analysis, systematic review of RCTs, or large RCTs with a very low probability (++) of bias whose results can be generalized to an appropriate population.
IN	High-quality (++) systematic review of cohort or case-control studies or High-quality (++) cohort or case-control studies with very low risk of bias or RCTs with low (+) risk of bias, the results of which can be generalized to the appropriate population .
WITH	Cohort or case-control or controlled trial without randomization with low risk of bias (+), whose results can be generalized to the appropriate population or RCTs with very low or low risk of bias (++ or +), whose results cannot be directly distributed to the relevant population.
D	Description of a case series or uncontrolled study or expert opinion

Classification

Classification of NSAID-IGP:

1. Etiological factor (the drug is indicated).
2. Process localization:

• stomach, most commonly antrum
• duodenum (rare)

3. Morphological variant: acute and/or chronic erosions or ulcers.
4. Dimensions of an erosive or ulcerative defect (size in cm).
5. Complications (with date): bleeding, penetration, perforation, etc.
6. By association with Helicobacter pylori infection ( H. pylori): associated or unassociated.

Diagnostics

METHODS, APPROACHES AND DIAGNOSIS PROCEDURES

Diagnostic criteria

Complaints patients for a burning sensation, a feeling of heaviness in the epigastric region, nausea, heartburn that occurs after taking NSAIDs. Less commonly, patients with EJP GD have intense pain in the epigastric region and dyspeptic disorders. Most often, pain syndrome occurs in patients with deep ulcers. To a certain extent, the phenomenon of "silent ulcers" is explained by the analgesic effect of NSAIDs, inhibition of the biosynthesis of prostaglandins - mediators of pain and inflammation.

Anamnesis
NSAID-IHPs are observed in patients over 65 years of age, more often in women, against the background of taking both non-selective and selective inhibitors of cyclooxygenase 1 or 2 (COX-1/2), low-dose aspirin (LDA) and anticoagulants (UDA) . Frequent history of smoking, alcohol consumption (UD B), peptic ulcer (PU) or gastrointestinal bleeding (GI) (UDA) . Relapses of NSAID-IHP occur with continued use and depend on the dose of drugs (UD B):

1. exceeding the standard dose by 1.5 times increases the risk by 2.8 times,
2. Exceeding the standard dose by 3 times increases the risk by 8 times.

Physical examination in patients with uncomplicated EJP, SO GDZ may reveal pain on palpation in the epigastric and / or pyloroduodenal region.
NB. Complications of NSAID-IHP.
Regardless of the duration of use and the route of administration, all NSAIDs, as well as NDA as part of antiplatelet therapy (AAT), are potentially capable of causing EJP with GDD. The most frequent and formidable complications of NSAID-IHP are gastrointestinal tract, the lethality of which is quite high. Signs of gastrointestinal tract are melena, anemia, pain in the upper abdomen, a history of gastrointestinal tract, GI, cardiovascular and cerebrovascular diseases, and diabetes mellitus. NSAIDs used for 0.5 to 3 months. NSAIDs and infection H. pylori are independent risk factors for gastrointestinal bleeding in patients over 60 years of age.

Laboratory research
General blood analysis. With a decrease in hemoglobin and red blood cells in patients with NSAID-IHP, it is recommended:
- determination of serum iron and ferritin in the blood;
- analysis of feces for occult blood.

Instrumental research:
Endoscopic characteristics of NSAID-IHP : hemorrhages, erosions, ulcers, bleeding. ENP are localized mainly in the antrum of the stomach. Acute ulcers are usually solitary, shallow and small in size, healing without scar formation. NADPCs are less common than YA, about 1:4.
According to the nature and quantity of ENP SO GDZ, detected during esophagogastroduodenoscopy (EGDS), a scoring of NSAID-IHP is carried out according to the Lanza scale (Table 3.).

Table 3. Endoscopic classification of Lanza score of lesions of the mucosal gland of the GDZ

With NSAID-IHP, there is an imbalance between the clinical picture and endoscopic changes. Therefore, EGDS is the only and accurate method for detecting ENP CO GDZ. It is also necessary to study the histological picture of biopsy specimens.

Morphological picture of NSAID-IHP- neutrophilic infiltration of interepithelial spaces and foveolar hyperplasia in the gastric mucosa.

H.pylori detected in 40-60% of patients taking NSAIDs. As a first-line diagnostic method, it is recommended to use a rapid urease test (RUT) in gastric biopsy specimens and the determination of antibodies (AT) to H. pylori in feces (stool test).

List of additional diagnostic measures:

• Ultrasound of the abdominal organs - according to indications (with concomitant pathology of the hapatobiliary system);
• biochemical blood test: total bilirubin and its fractions, total protein, albumin, cholesterol, ALT, AST, glucose, amylase - (with concomitant pathology of the hapatobiliary system);
• radiography of the stomach with barium contrast is performed with pyloric stenosis, the presence of contraindications and the patient's refusal from endoscopy.

Indications for expert advice

Indications	Clinical signs	Expert advice
Ulcer or erosion of the stomach, complicated by gastrointestinal tract	Pallor of the skin, tachycardia, weakness, dizziness, melena, vomiting of coffee grounds, hypotension + Gregersen reaction (feces for occult blood) KLA - Decrease in the level of hemoglobin, the number of erythrocytes, Blood BHA - decreased serum iron	Hematologist Surgeon,
Gastric ulcer complicated by CO perforation	Symptoms of an acute abdomen - dagger abdominal pain, board-like abdomen, cold sticky sweat, tachycardia, decreased blood pressure, + see Shchetkin Blumberg,	Surgeon
pyloric stenosis	Noise splashing in the abdomen after taking liquid, food, severe weakness after eating, sweat, pallor, weight loss. - Narrowing of the pyloric canal on HDD radiography with barium contrast	Surgeon

Diagnostic algorithm: (scheme)


Figure 1. Algorithm for diagnosing NSAID-induced gastropathy

Differential Diagnosis

Differential diagnosis and rationale for additional studies
The main criteria for NSAID-IHP are the patient's advanced age, the details of the anamnesis, the details of which make it possible to establish the fact of taking NDA as part of AAT in patients with coronary heart disease (CHD) and arterial hypertension (AH), as well as taking NSAIDs in patients with rheumatic diseases, collagenoses, with diseases of the musculoskeletal system and in neurological patients. When verifying the diagnosis, one should take into account the spectrum of GDZ diseases that occur with symptoms of gastric dyspepsia, abdominal pain. Differential diagnosis and rationale for additional investigations are presented in Table 4.

Table 4. Differential diagnosis of NSAID gastropathy

Diagnosis	Rationale for differential diagnosis	Surveys	Diagnosis Exclusion Criteria
Stress erosions and ulcers of the GDZ		EGDS - acute ENP of various departments of the GDZ. (-) tests for H.pylori (+/-) reaction to fecal occult blood	vomiting "coffee grounds", melena, signs of anemia. The nature of the pain syndrome Causal factors: t severe trauma, massive burns, sepsis, shock, injuries, operations, myocardial infarction, multiple organ failure
Peptic ulcer of the duodenum	Abdominal pain and/or feeling of heaviness in the stomach and rapid satiety after eating	KLA: iron deficiency anemia (IDA) BHA: Decreased serum iron levels EGDS - duodenal ulcer, Histology of biopsy specimens - Chronic antral gastritis and duodenitis. (+/-) reaction to occult blood in the feces, (+/-) tests for H. pylori	Young age, more often men, asthenic physique, The nature of the pain syndrome - late, "hungry" after 2-3 hours, night pain in the pyloroduodenal zone, seasonal (spring-autumn) nature of relapses (+/-) melena
Stomach ulcer	Abdominal pain and/or feeling of heaviness in the stomach and rapid satiety after eating	KLA: iron deficiency anemia (IDA) BHA: Decreased serum iron levels X-ray - with pyloric stenosis EGDS - Ulcerative defect more often on the lesser curvature of the stomach, surrounded by an inflammatory shaft, covered with fibrin Biopsy histology - antral gastritis, moderate atrophy in the fundus (+/-) tests for H. pylori (+/-) reaction to occult blood in the feces,	Patients over 40 years of age, both sexes, The nature of the pain syndrome - pain in the epigastrium "early" - 1-1.5 hours after eating, poor appetite, weight loss (+/-) vomiting "coffee grounds"

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Treatment

Drugs (active substances) used in the treatment

Aluminum hydroxide (Aluminium hydroxide)

Amoxicillin (Amoxicillin)

Aceclofenac (Atseklofenak)

Acetylsalicylic acid (Acetylsalicylic acid)

Diclofenac (Diclofenac)

Ibuprofen (Ibuprofen)

Calcium carbonate (Calcium carbonate)

Ketoprofen (Ketoprofen)

Ketorolac (Ketorolac)

Clarithromycin (Clarithromycin)

Clopidogrel (Clopidogrel)

Lansoprazole (Lansoprazole)

Levofloxacin (Levofloxacin)

Magnesium hydroxide (Magnesium hydroxide)

Meloxicam (Meloxicam)

Metronidazole (Metronidazole)

Misoprostol (Misoprostol)

Naproxen (Naproxen)

Sodium alginate (Sodium alginate)

Sodium bicarbonate (Sodium hydrocarbonate)

Nimesulide (Nimesulide)

Omeprazole (Omeprazole)

Pantoprazole (Pantoprazole)

Piroxicam (Piroxicam)

Ranitidine (Ranitidine)

Ticagrelor (Ticagrelor)

Famotidine (Famotidine)

Celecoxib (Celecoxib)

Etoricoxib (Etorikoksib)

Groups of drugs according to ATC used in the treatment

Treatment (ambulatory)

TACTICS OF TREATMENT AT THE OUTPATIENT LEVEL

Non-drug treatment: mode, diet (Table 5):

Excluded

Allowed

juice products and dishes (meat, fish, mushroom broths) connective tissue products (cartilage, poultry and fish skin, sinewy meat) fatty meats and fish marinades, pickles, seasonings fresh bread, wholemeal dough products, millet pancakes, pies, cakes vegetables containing fiber (peas, beans, beans, turnips), mushrooms unripe and fruits and berries with rough skins, acidic fruit juices chocolate, cocoa, coffee, strong tea, carbonated drinks

vegetable, cereal, milk soups boiled lean meat and fish, soft-boiled egg, steam omelet, fresh non-acidic cottage cheese, cheeses, dried wheat bread white crackers, lean cookies, well-boiled porridge, vermicelli and white flour noodles, vegetable and mashed potatoes, salads, vinaigrettes with vegetable oil, non-acidic fruit juices pulp milk and dairy products (ryazhenka, yogurt) alkaline mineral waters without carbonic acid, weak tea.

Recommended:

• a complete and varied diet;
• fractional mode, up to 6 times a day, in small portions;
• restriction of gastric stimulants
• limiting products that stay in the stomach for a long time;
• exclusion of hot and cold dishes;
• food should be liquid, mushy and dense
• food should be boiled and pureed.

Medical treatment
In the treatment of NSAID-IHP, it is recommended: proton pump inhibitors (PPIs), histamine H 2 receptor blockers (BN 2 RG), prostaglandin E2 analogs ( UD A) .

For the treatment and prevention of NSAID-IHP drugs of choice are IPP ( omeprazole , lansoprazole , esomeprazole ) . The incidence of ulcers, multiple erosions and reflux esophagitis while taking pantoprazole is lower than while taking misoprostol (p=0.005). In patients treated with NSAIDs and with a history of GI, the recurrence rate was significantly lower in those treated with lansoprazole compared to patients who did not receive PPIs (p = 0.008). The administration of omeprazole reduces gastrointestinal symptoms and has better efficacy in the treatment of NSAID-IHP ( UD A). Therefore, there is not much difference in efficacy between different PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole esomeprazole). All available PPIs at recommended doses are equally effective.

In patients with coronary artery disease taking NDA and clopidogrel, it is recommended BN 2 RG as an alternative therapy for PPIs. The use of these drugs suppresses the production of stomach acid by 37-68% within 24 hours. Despite the preferred recommendations for the use of PPIs in the prevention of NDA-associated GIB, there is conclusive evidence that BN 2 RGs are safe and effective even at high doses for the treatment and prevention of NSAID-ISHGP ( UD A).

High efficacy of BN 2 RG famotidine in the treatment and prevention of NSAID-IHP. Famotidine reduces the frequency and significantly reduces the severity of both pain symptoms of dyspepsia, reduces the frequency of NSAID-IG UD A.
BN 2 RG is not significantly associated with the side effects that PPIs have - an increased risk of fractures , development of pneumonia and colitis C. difficile .
Treatment with PPIs or BN 2 WG should be continued for 4 to 8 weeks. Cancellation of NSAIDs without adequate treatment in 60% of patients does not lead to healing of ulcers and erosions within the next 3 months .

Prostaglandin analog (PG) m isoprostol, by stimulating the secretion of mucus, bicarbonate and stabilizing the barrier function, it protects the GDZ mucosa, reduces the frequency of NSAID-IHP by about 40% ( UD B). However, due to poor tolerance, frequent diarrhea and abdominal pain, and high cost, these drugs have not been widely used in clinical practice.

eradication therapy. Synergistic damaging effect of NSAIDs and NDA and infection H. pylori recognized at SO GDZ . According to the recommendations of the European working group "Maastricht-5" (2015) H.Rylori considered as an independent risk factor for the development of NSAID-IHP. In order to reduce the risk of EAP with GDZ associated with taking NSAIDs and LDA, it is recommended to carry out eradication therapy before starting treatment with NSAIDs ( UD A):

1. First line therapy (14 days):

• 3-component scheme: [PPI 40 mg + amoxicillin 1000 mg + clarithromycin 500 mg] x 2 times a day;

or

• bismuth-free quadruple therapy: [PPI 40 mg + amoxicillin 1000 mg + clarithromycin 500 mg + nitromidazole 500 mg] x 2 times a day.

If clarithromycin is not effective or there are undesirable side effects, 2nd line eradication therapy is used:

1. Second line therapy (14 days):

• 3-component scheme: [PPI 40 mg + amoxicillin 1000 mg + fluoroquinolone 500 mg] x 2 times a day.

To improve the effectiveness of eradication, it is recommended:

• administration of a double dose of PPI 2 times a day.
• increase in the duration of triple therapy from 7 to 10-14 days .

N.B. Treatment of complications
At development of housing and communal services antisecretory therapy is an important part of conservative tactics, since its use reduces mortality. In the first three days, intravenous infusions of a standard or double dose of PPI are carried out. From the fourth day, they switch to the appointment of PPIs orally in a standard dose. the effectiveness of BN 2 RG and PPIs is the same for the treatment and/or prevention of recurrent GIB in regular users of LDA or NSAIDs with a high risk of complications. It is possible to achieve a decrease in intragastric pH only with intravenous administration of sufficiently large doses of PPI or BN 2 RG. Temporary interruption of anticoagulant therapy, administration of fresh frozen plasma, vitamin K is recommended in all patients with GIB. (UD A).

Complementary medicines
As additional medicines for NSAID-IHP, nonabsorbable aluminum-magnesium antacids are used. These groups of drugs are recommended for use by patients only as a symptomatic therapy to eliminate or reduce heartburn ( UD C).

Scroll the main and additional drugs recommended for the treatment of NSAID-IHP are presented in Tables 6 and 7 (respectively).

Table 6. List of essential drugs recommended for the treatment of NSAID-IHP

№/№	International nonproprietary name (INN)	Release form	Way introductions	one-time dose	Reception frequency	Duration of treatment	UD
	medicinal group - proton pump inhibitors
1	Omeprazole	-Capsules (including enteric, with prolonged release) - 10 mg, 20 mg, 40 mg - Lyophilisate for solution for infusion, 40 mg.	oral	20 mg	2 times a day 1-2 times a day	4-8 weeks 3-4 days
2	Lansoprazole	-Capsules (including modified release) 15 mg and 30 mg	oral	15 mg	2 times a day	4-8 weeks	A
3	Pantoprazole	- Tablets, coated (including enteric) with delayed release 20 mg and 40 mg - Powder for solution for intravenous administration, 40 mg	oral To prepare a solution for intravenous administration	20 mg 40 mg	2 times a day. 1 time per day	4-8 weeks 3-4 days
	medicinal group - Histamine H2 receptor blockers
4	famotidine	- Tablets, coated (including film) 20 mg and 40 mg - Freeze-dried powder 20 mg	oral To prepare a solution for intravenous administration	20 mg 20-40 mg	2 times a day. 1 time per day	4-8 weeks 4-5 days
5	Ranitidine	- Tablets, coated (including film) 150mg and 300mg	oral	150 mg	2 times a day	4-8 weeks	A

Table 6. List of essential drugs recommended for the treatment of NSAID-IHP (continued)

№/№	INN	Release form	Way introductions	one-time dose	Reception frequency	Duration of treatment	UD
	medicinal group - antimicrobials ( with the synergistic effect of NSAIDs in H. pylori infection )
6	Amoxicillin	Tablets, incl. coated, dispersible; capsules 500mg, 1000mg	oral	1000 mg	2 times a day	14 days	A
7	Clarithromycin	Tablets, incl. modified release 500mg	oral	500 mg	2 times a day	14 days	A
7	Metronidazole	Tablets 250 mg	oral	250 mg	4 times a day	14 days	A
9	Levofloxacin*	Film-coated tablets 500mg	oral	500 mg	2 times a day	14 days	WITH
Note: * (only for confirmed resistance to other antimicrobials)

Table 7. List of additional drugs recommended for the treatment of NSAID-IHP

№/№	INN	Release form	Way introductions	single dose	Reception frequency	Duration treatment	UD
medicinal group- antacids
1	Magnesium hydroxide and aluminum hydroxide	Tablets, incl. chewable	oral	1-2 tab 1 dess.spoon	only for heartburn	on demand	WITH
2	Calcium carbonate + sodium bicarbonate + sodium alginate	Chewable tablets Suspension for oral administration	oral	1-2 tab 1 dess.spoon	only for heartburn	on demand	WITH

Surgical intervention: No.

Further management
Based on clinical and epidemiological studies, for patients with NSAID-IHP, international experts have approved management tactics with the highest degree of certainty ( UD A) :

• consider the possibility of prescribing NSAIDs only when necessary, taking into account age, history of GU, GIB;
• with long-term use of NSAIDs, patients are recommended to undergo endoscopic control once a year;
• in the presence of symptoms of gastric dyspepsia and / or abdominal pain, conduct endoscopy and laboratory tests before treatment and 3 months after starting NSAIDs.

Tactics of managing patients depending on the nosology:

• at peumatological and neurological diseases NSAIDs are prescribed despite various gastrointestinal complications. All NSAIDs inhibit the activity of both COX isoforms differently, therefore, selectivity determines their safety (Table 9).

Table 9. Classifications of NSAIDs

It was found that the relative risk of developing NSAID-IHP when taking ibuprofen is 1.19, piroxicam - 1.66, diclofenac 1.73, naproxen - 1.83. Selective COX-2 inhibitors that are not related to coxibs include meloxicam, etodolac, nimesulide, which are less likely to cause EOR with GDZ than piroxicam and naproxen. Therefore, the consensus of the American College of Gastroenterology recommends the use of non-selective NSAIDs in low-risk patients and COX-2 inhibitors in high-risk patients. If problems arise in the treatment of non-selective NSAIDs, they can be replaced with a COX-2 inhibitor.

If it is impossible to cancel NSAIDs, omeprazole 20 mg 2 times a day or lansoprazole 30 mg 2 times a day are prescribed simultaneously; or famotidine 20 mg twice daily or ranitidine 150 mg twice daily; or misoprostol 200 micrograms four times a day. Treatment continues 4-8 weeks (UD A).

For NSAID-IHP patients who need to restart NSAIDs, it is recommended that a daily PPI be given along with COX-2. In patients with bleeding ulcers associated with LDA, long-term daily PPI therapy should also be provided. (UD A).
- in cardiovascular diseases(CHD, AH), after myocardial revascularization, in cerebrovascular diseases, NDA are important for the treatment and prevention of thrombotic complications. However, even enteric-soluble forms of ASA (Acetylsalicylic acid) or gastroprotective buffer forms of ASA (Acetylsalicylic acid with Mg hydroxide) do not exclude the possibility of NSAID-IHP . Therefore, in patients with coronary artery disease who take long-term NDA with clopidogrel (or ticagrelor), in the presence of ENP CO GDZ (UD A), recommended:

• resolve the issue of the possibility of canceling ASA drugs;

• if it is impossible to cancel ASA, the standard daily dose of PPI is doubled, while pantoprazole 40 mg 2 times a day is recommended, which has a low affinity for the cytochrome P450 system;
• in the presence of urgent indications for stenting or coronary artery bypass grafting, it is necessary to repeat EGDS after 2 weeks and, in the absence of ENP, proceed to invasive restoration of coronary blood flow;
• biopsy of SO GDZ is contraindicated in case of hypocoagulation in patients with coronary artery disease receiving NDA as part of AAT;

• in the postoperative period, patients with coronary artery disease receiving AAT for more than 1 year are recommended to take prophylactic courses of pantoprazole (20 mg / day) for 2 weeks every quarter.

Indicators of the effectiveness of treatment and the safety of diagnostic methods

• Relief of clinical symptoms of dyspepsia,
• improving the quality of life of patients,
• disappearance of endoscopic signs of inflammation,
• regeneration of erosive and ulcerative lesions of the GDZ,
• elimination of H. pylori;

Hospitalization

INDICATIONS FOR HOSPITALIZATION WITH INDICATING THE TYPE OF HOSPITALIZATION

Indications for planned hospitalization: No

Indications for emergency hospitalization:
Emergency hospitalization is carried out in patients with NSAID-IHP with complicated forms of ENP SO GDZ:

• gastrointestinal bleeding;
• perforation;
• decompensated pyloric stenosis;
• penetration.

Operations are performed in accordance with current protocols.

Information

Sources and literature

1. Minutes of the meetings of the Joint Commission on the quality of medical services of the Ministry of Health of the Republic of Kazakhstan, 2018
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PPI versus Histamine H2 Receptor Antagonists for Prevention of Upper Gastrointestinal Injury Associated with Low-Dose Aspirin:Systematic Review and Meta-analysis. //PLOS One. 2015;10(7): e0131558. 25. Stupnicki T., Dietrich K., Gonzalez-Carro P. et al. Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients //Digestion. 2003;68(4):198–220. 26. Lai K., Lam S., Chu K. Lansoprazole for the prevention of recurrences of ulcer complication from long-term low-dose aspirin use // N.Engl.J.Med.2002;346: 2033–2038. 27. Tamura A., Murakami K., Kadota J. Prevalence of gastroduodenal ulcers/erosions in patients taking low-dose aspirin with either 15 mg/day of lansoprazole or 40 mg/day of famotidine: the OITA-GF study 2. / / BMC Res Notes. 2013;6:116. 28. Scally B1, Emberson JR2, Spata E2, Reith C3, Davies K3, Halls H3, Holland L3, Wilson K3, Bhala N4, Hawkey C5, Hochberg M6, Hunt R7, Laine L8, Lanas A9, Patrono C10, Baigent C11. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomized trials. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):231-241. 29. Chan F.K., Kyaw M., Tanigawa T. et al. Similar Efficacy of Proton-Pump Inhibitors vs H2-Receptor Antagonists in Reducing Risk of Upper Gastrointestinal Bleeding or Ulcers in High-Risk Users of Low-Dose Aspirin. gastroenterology. 2017; 152 (1): 105-110 , Sperling L.S., Tomaselli G.F. ACCF/ACG/AHA. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010;15:2533–2549. 31. Koch M., Dezi A., Ferrario F., Capurso I. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med. 1996;15:2321–2332. 32. Szabó I.L., Mátics R., Hegyi P., Garami A., Illés A., Sarlós P., Bajor J., Szűcs A., Mosztbacher D., Márta K., Szemes K., Csekő K., Kővári B., Rumbus Z., Vincze A. PPIs Prevent Aspirin-Induced Gastrointestinal Bleeding Better than H2RAs. A Systematic Review and Meta-analysis // J Gastrointestin Liver Dis. 2017, 26(4): 395-402. 33. Chen W.C., Li Y.D., Chiang P.H., Tsay F.W., Chan H.H., Tsai W.L., Tsai T.J., Wang E.M., Lai K.H. Comparison of proton pump inhibitor and histamine-2 receptor antagonist in the prevention of recurrent peptic ulcers/erosions in long-term low-dose aspirin users: a retrospective cohort study. //Biomed Res Int. 2014; 2014:693567. 34. Tuskey A., Peura D. The use of H2 antagonists in treating and preventing NSAID-induced mucosal damage // Arthritis Res. Ther. 2013;15(Suppl. 3):S6. 35. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. // Cochrane Database Syst Rev. 2002;15:CD002296. 36. Liu J, Sun D, ​​He J, Yang C, Hu T, Zhang L, Cao H, Tong AP, Song X, Xie Y, He G, Guo G, Luo Y, Cheng P, Zheng Y. Gastroprotective effects of several H2RAs on ibuprofen-induced gastric ulcer in rats. life sci. 2016 Mar 15;149:65-71. 37. Lazebnik L. B., Drozdov V. N., Kim V. A. Efficacy of famotidine in the prevention of NSAID-gastropathy, results of the Russian multicenter study of barrier-i (protection of the gastric mucosa from non-steroidal anti-inflammatory drugs). Central Research Institute of Gastroenterology, Moscow // Experimental and Clinical Gastroenterology. 2009.-№2. – p.3-9 38. Eom C.S., Park S.M., Myung S.K., Yun J.M., Ahn J.S. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. // Ann Fam Med. 2011;15:257–267. 39. Rodriguez L.A, Ruigomez A., Wallander M.A., Johansson S. Acid-suppressive drugs and community-acquired pneumonia. // Epidemiology. 2009;15:800–806 40. Jayatilaka S., Shakov R., Eddi R., Bakaj G., Baddoura W.J., DeBari V.A. Clostridium difficile infection in an urban medical center: five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. //Ann Clin Lab Sci. 2007;15:241–247. 41. Lems WF1, Kuipers EJ. //Ned Tijdschr Geneeskd. 2010;154(45):A2663. 42. Wen L. Upper Gastrointestinal Complications and Cardiovascular/ Gastrointestinal Risk Calculator in Patients with Myocardial Infarction Treated with Aspirin // Chin Med J (Engl). 2017;130(16):1909-1913. 43. Gralnek I.M., Dumonceau J.M., Kuipers E.J. et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. //Endoscopy. 2015;47:a1–a46. 44. Karaseva G.A. NSAID-induced gastropathy: from understanding the mechanisms of development to the development of a strategy for prevention and treatment // Medical News. - 2012. - No. 8. - S. 21-26. 45. Tsai YW, Wen YW, Huang WF, Chen PF, Kuo KN, Hsiao FY. Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients with previous gastrointestinal bleeding. //J Gastroenterol. 2011 Jan;46(1):39-45. 46. ​​Lanas A. Advances in gastrointestinal bleeding. // Gastroenterol Hepatol. 2016 Sep;39 Suppl 1:53-61. 47. Radaelli F., Paggi S., Terruzzi V. et al. Management of warfarin-associated coagulopathy in patients with acute gastrointestinal bleeding: a cross-sectional physician survey of current practice. //Dig LiverDis. 2011;43:444–447. 48. Maev I.V., Samsonov A.A., Andreev D.N. The role and place of antacids in modern algorithms for the treatment of acid-related diseases // Farmateka. - 2013. - No. 2. - S. 66–72. 49. Wongrakpanich S., Wongrakpanich A., Melhado K., Rangaswam J. A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly //Aging Dis. 2018; 9(1): 143–150. 50. Hunt R., B Lazebnik L., C Marakhouski Y., Manuc M., Gn R., S Aye K., S Bordin D., V Bakulina N., S Iskakov B., A Khamraev A., M Stepanov Y., Ally R., Garg A. International Consensus on Guiding Recommendations for Management of Patients with Nonsteroidal Antiinflammatory Drugs Induced Gastropathy-ICON-G. //Euroasian J Hepatogastroenterol. 2018 Jul-Dec;8(2):148-160. 51. Chan FKL1, Ching JYL2, Tse YK2, Lam K2, Wong GLH2, Ng SC2, Lee V3, Au KWL4, Cheong PK2, Suen BY4, Chan H2, Kee KM2, Lo A2, Wong VWS2, Wu JCY2, Kyaw MH2. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet. 2017 Jun 17;389(10087):2375-2382. 52. Lazebnik L.B. , Tkachenko E.V., Abdulkhakov R.A., Bordin D.S., Grinevich V.B., Minushkin O.N., Pasechnikov V.D., Radchenko V.G., Rustamov M.N., Sayfutdinov R.G., Samsonov A.A., Sarsenbayeva A.S., Sitkin S.I., Starostin B.D.. Yakovenko E.P. Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases. Chronic gastritis // Bulletin of a practical doctor. Special issue. - 2013. - No. 3. pp. 12-14.] 53. Fletcher E.H., Johnston D.E., Fisher C.R., et al. Systematic review: Helicobacter pylori and the risk of upper gastrointestinal bleeding risk in patients taking aspirin. //Aliment Pharmacol. Ther. 2010;32:831–39. 54 Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. // Gastroenterology. 2017;152(4):706–715. 55. Laine L, Jensen DM. Management of patients with ulcer bleeding. // Am J Gastroenterol. 2012;107(3):345–361. 56. Takeuchi K. Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility // World J Gastroenterol. 2012; 18:2147–2160. 57. Inger L. Meek, Mart A.F.J. van de Laar, and Harald E. Vonkeman* Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks //Pharmaceuticals (Basel). 2010 Jun; 3(7): 2146–2162. 58. Xue W.Q., Cai Y.X., Liu J., Zhang B. 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Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries // World J Gastroenterol. 2015;21(17): 5382-92. 64. Scheiman J.M., Hindley C.E. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events //Clin Ther. 2010;32(4):667-77.

Information

ORGANIZATIONAL ASPECTS OF THE PROTOCOL

List of protocol developers with qualification data:

1. Iskakov Baurzhan Samikovich - Doctor of Medical Sciences, Professor, Head of the Department of Internal Diseases No. 2 of JSC "National Medical University", Deputy Chairman of the National Association of Gastroenterologists of the Republic of Kazakhstan, therapist of the highest qualification category.
2. Bektaeva Roza Rakhimovna - Doctor of Medical Sciences, Professor, Head of the Department of Gastroenterology and Nutrition of NJSC "Astana Medical University", Chairman of the National Association of Gastroenterologists of the Republic of Kazakhstan, therapist of the highest qualification category;
3. Aldasheva Zhanna Akhmetovna - Candidate of Medical Sciences, Professor, Head of the Department of Gastroenterology, Nutrition with a Course of Gerontology
4. Aldiyarova Malika Abdulzhapparovna - Candidate of Medical Sciences, Head of the Department of Propaedeutics of Internal Diseases and Nursing of the National Educational Institution "Kazakhstan-Russian Medical University", gastroenterologist of the highest qualification category; JSC "Kazakh Medical University of Continuing Education";
5. Makalkina Larisa Gennadievna - Candidate of Medical Sciences, Associate Professor of the Department of Clinical Pharmacology of the Internship at NJSC "Astana Medical University".

Indication of no conflict of interest: No.

Reviewers:

1. Shipulin Vadim Petrovich - Doctor of Medical Sciences, Professor, Head of the Department of Internal Medicine No. 1 of the National Medical University named after A.A. Bogomolets, Kiev, Ukraine;
2. Bimbetov Bakhytzhan Ryskulovich - doctor of medical sciences, professor, hepatologist of the Republican State Enterprise on the REM "Medical Center of the Administration of the President of the Republic of Kazakhstan".

Indication of the conditions for revising the protocol:

revision of the protocol 5 years after its publication and from the date of its entry into force or in the presence of new methods with a level of evidence

Attached files

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Irina Alexandrovna Zborovskaya - Director of the Federal Budgetary State Institution "Scientific Research Institute of Clinical and Experimental Rheumatology" of the Russian Academy of Medical Sciences, Professor of the Department of Hospital Therapy with a Course of Clinical Rheumatology, Faculty of Postgraduate Medical Education, Volgograd State Medical University, MD. Treatment of gastropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is not only an urgent problem, but also a difficult task, since most patients fail to stop taking NSAIDs due to the high risk of exacerbation of the underlying disease, for which the patient systematically takes them. In the tactics of managing such patients who are diagnosed with gastroduodenal complications or have risk factors for NSAIDs - gastropathy, two interrelated approaches can be distinguished:

1. Optimizing the use of NSAIDs
2. Antiulcer therapy, which should be differentiated, depending on whether it is aimed at the prevention or treatment of NSAIDs - gastropathy.

I. Optimization of the use of NSAIDs includes the following main points 1. If any gastroenterological side effects appear, it is necessary to decide whether it is advisable to continue taking NSAIDs. Cancellation of the drug, although it does not lead to a "cure", but increases the effectiveness of antiulcer therapy and reduces the risk of recurrence of the erosive and ulcerative process in the gastrointestinal tract. 2. If it is impossible to completely stop taking NSAIDs, the dose should be reduced as much as possible and treatment should be carried out under endoscopic control. 3. An effective way to reduce the risk of NSAIDs - gastropathy is the use of NSAIDs with the least side effects (ibuprofen, diclofenac), as well as the use of drugs with higher selectivity for COX-2 (Movalis, Nimesulide = Nise, Celebrex). So, these are the main provisions of treatment optimization. It should be noted that the transition to parenteral, rectal administration of NSAIDs, as well as the use of drugs with intestinal coating does not reduce the risk of erosive and ulcerative lesions and does not significantly affect the rate of scarring against the background of antiulcer therapy, which once again confirms the position: gastropathy induced by NSAIDs should be considered not a local, but a systemic side effect of NSAIDs, associated primarily with the suppression of prostaglandin synthesis and only then with a direct damaging effect on the mucosa of the gastrointestinal tract (gastrointestinal tract). II. Antiulcer therapy in the treatment of NSAIDs - gastropathy. 1. In the treatment of NSAIDs - gastropathy, based on all of the above, the use of 3 groups of drugs 1 g is pathogenetically justified. Synthetic analogues of prostaglandin E 1: misoprostol, Cytotec, Cytotec. 2 gr. - Blockers of H 2 - histamine receptors: ranitidine, famotidine (II generation), kvamatel (III generation). 3 gr. – Proton pump inhibitors: omeprazole (Omez), lansoprazole (Lanzap), rabeprazole (Pariet). The 2nd and 3rd groups of drugs are a class of antisecretory agents. The rationale for prescribing antisecretory drugs that block the production of hydrochloric acid is: firstly: a decrease in the reverse diffusion of hydrogen ions and their damaging effect on the mucous membrane; secondly: a drop in the activity of pepsin or its inactivation with an increase in intragastric pH to 4.0 and above, which leads to a decrease in the aggressive properties of gastric juice; thirdly: at a high intragastric pH level, the diffusion of hydrogen ions into the mucous membrane drops sharply. Long-term suppression of gastric acid production while maintaining an intragastric pH level above 4.0 and especially at 6.0 is one of the main tasks in the treatment of gastropathy associated with the use of NSAIDs, which is successfully solved by antisecretory drugs. It has been established that the suppression of acid production leads to scarring of ulcers and epithelialization of gastric erosions, even in patients who continue to take NSAIDs. In the treatment of gastropathy, the use of synthetic analogues of prostaglandin E 1 (misoprostol) is justified, which can be considered a means of replacement therapy. The effect of misoprostol is related to its ability to stimulate bicarbonate and mucus production, maintain normal local blood flow and maintain mucosal integrity as a protective barrier. Misoprostol enhances mucosal epithelial proliferation in response to injury. 2. To evaluate and confirm this position, it is necessary to remember how the parietal cell that synthesizes hydrochloric acid works. Very briefly! The figure schematically shows the mechanism of the parietal cell, which is directly responsible for acid production. On the basolateral membrane of the parietal cell, there are a number of receptors (M-cholinergic receptors, H 2 -histamine receptors, gastrin receptors) that regulate the secretory activity of the cell. Stimulation of these receptors leads (through a series of intermediate reactions) to stimulation of the proton pump (PP), i.e. activity of H + K + ATP-ase, which is involved in the final stage of HCl synthesis and, due to the energy of ATP, transports hydrogen ions into the lumen of the gland from the cell, exchanging them for K ions from the extracellular space. H + ions in the lumen of the gland combine with Cl ions and HCl is formed. 3 The most effective drugs in the treatment of gastroduodenal ulcers and erosions are proton pump inhibitors (PPIs). Scheme: Regulation of acid production and pharmacological targets for antisecretory therapy. 1) PPI inhibiting the activity (namely) of the enzyme H + K + ATP-ase (hydrogen-potassium ATP-ase), thereby blocking the final stage of the synthesis of hydrochloric acid. As a result, there is a significant decrease in the level of basal and stimulated secretion, regardless of the stimulating factor. This distinguishes PPIs from other antisecretory drugs, including H2 receptor blockers, which block only one of the many mechanisms of HCl (hydrochloric acid) secretion. The high efficacy of PPIs, superior to that of histamine H2-receptor blockers and misoprostol, has been confirmed by numerous studies that meet the requirements of evidence-based medicine. 2) In the last 5 years, a number of large-scale clinical studies have been conducted to study the comparative effectiveness of the main groups of drugs used in the treatment of NSAIDs - gastropathy. Of particular interest are the international studies of OMNION and ASTRONAVT. The OMNION study compared (Table 1) the effectiveness of Omez and misoprostol in the treatment of ulcers and erosions caused by NSAIDs according to 93 centers in European countries, as well as the USA, Canada, Australia and New Zealand. Table 1. Healing (in %) of erosive and ulcerative lesions of the stomach and duodenum caused by NSAIDs after 8 weeks of treatment. The study included patients who constantly take NSAIDs (mainly with RA and OA), the effect of treatment was evaluated after 8 weeks. The results of the studies showed that Omez at a dose of 20 and 40 mg is significantly more effective than misoprostol for scarring of gastric ulcers and, especially, in scarring of duodenal ulcers (see table 1). It is interesting to note that the healing of gastroduodenal erosions is more active with the use of misoprostol, the % of healing is 87, versus 77-79 during treatment with Omez. Another international study, ASTRONAVT (according to 73 research centers from 14 countries), compared the effectiveness of Omez and ranitidine in the treatment of ulcers and erosions caused by NSAIDs. table 2 Healing (%) of erosive and ulcerative lesions of the stomach and duodenum caused by NSAIDs after 8 weeks of treatment. In this study, Omez was also more effective in healing gastric and duodenal ulcers than ranitidine (see Table 2). It should also be noted that when prescribing H 2 -receptor blockers of histamine of the III generation of quamatel (famotidine), the percentage of ulcer healing compared with ranitidine (II generation) is significantly higher and amounts to 84 in GU and 86 in DU, which is somewhat lower than while taking Omez. Thus, the results of international studies evaluating the effectiveness of the treatment of gastropathy induced by NSAIDs give reason to recommend (in the presence of gastric and duodenal ulcers) PPI: Omez 20 mg 2 r. or lanzap 30 mg 2 r / day, and in the treatment of erosions, along with Omez and lanzap, ranitidine 150 mg 2 r. or kvamatel 20 mg 2 r. or misoprostol 200 mcg qid. Treatment should be carried out for an average of 4 weeks, then it is advisable to reduce the daily dose of the drug by 2 times and continue taking it for prophylactic purposes throughout the entire period of taking NSAIDs. Side effects of ongoing therapy are observed much more often in patients taking misoprostol (abdominal pain, flatulence, diarrhea). 4. If Helicobacter pylori is detected in patients with gastropathy in the mucous membrane of the antrum of the stomach, it is advisable, in accordance with the Maastricht Agreement of 2000, to carry out eradication therapy by adding antibiotics. Carrying out this therapy, according to most researchers, is especially appropriate in those patients who have a history of indications of the presence of peptic ulcer, since the destruction of Helicobacter pylori in such cases reduces the risk of its exacerbation while taking NSAIDs. In order to eradicate Helicobacter pylori, one of the standard schemes is used: The first scheme (3 drugs). 1) PPI: Omez 20 mg 2 p. or lanzap 30 mg bid 2) Clarithromycin 500 mg twice a day 3) Amoxicillin 1000 mg 2 times a day. The course of treatment is 7 days, in case of ineffectiveness, it is prescribed The second scheme (4 drugs): 1) Omez 20 mg 2 p. or lanzap 30 mg x 2 times a day. 2) De-nol 120 mg 4 times a day 3) Metronidazole 500 mg 3 times a day. 4) Tetracycline 500 mg 4 times a day The duration of therapy is 7 days. In some cases, taking into account the financial capabilities of the hospital and the patient, with somewhat less success, Omez can be replaced with ranitidine 150 mg 2 times a day in the indicated schemes. or quamatel 20 mg twice a day. In recent years, H. pylori eradication schemes have recommended the use of a new generation PPI - rabeprozole (pariet) at 20 mg x 2 r. / Day.
Pariet, as a basic component of anti-Helicobacter pylori regimens, compares favorably with other PPIs by its ability to provide a fast and powerful antisecretory effect. Pariet is converted to its active form faster than omeprazole and lansoprazole (i.e. other PPIs), which explains the faster onset of its inhibitory effect on HCl secretion (from day 1) compared to omeprazole and lansoprazole. Intragastric pH in the treatment of pariet is significantly higher than in the treatment of other PPIs, which is sufficient and optimal for the development of synergism between PPIs and antibacterial drugs in the eradication of H. pylori. 5. So, according to modern concepts, the algorithm for the treatment of NSAIDs - gastropathy includes the following provisions: 1) Decide on the possibility of canceling NSAIDs. 2) If available, standard-dose PPIs or standard- or double-dose histamine H2-receptor blockers or misoprostol 800 mg/day should be given concomitantly. 3) If it is impossible to cancel NSAIDs, prescribe PPIs. 4) Treatment lasts 4-8 weeks and is combined with H. pylori eradication. according to indications. 6. Prevention of NSAIDs - gastropathy. Prophylactic administration of antiulcer drugs is indicated for patients who have an increased risk of developing erosive and ulcerative lesions of the stomach and duodenum.
There are 10 main risk factors. A. Age B. Preceding and concomitant diseases C. Type and dose of the drug D. Duration of NSAID treatment E. Relationship of NSAID intake with food intake F. Smoking G. Alcohol intake H. Concomitant use of other drugs I. Gender K. The presence of Helicobacter pylori Since their influence is ambiguous, it is necessary to dwell on each factor. A. Age. The incidence of NSAIDs - gastropathy in elderly patients is 4 times higher than in young people, which may be due to: a) the greater severity of the underlying disease and b) the presence of concomitant pathology B. Preceding and concomitant diseases a) The presence of a history of ulcer ( in combination with old age) increases the likelihood of developing erosive and ulcerative lesions of the stomach and duodenum 12-14 times. b) The risk of developing NSAIDs - gastropathy increases in the presence of other diseases, such as: PERB, SJS, cirrhosis with portal hypertension, CVS disease. C. Type and dose of the drug a) The highest risk of developing gastropathy when taking piroxicam, indomethacin, ketoprofen. b) Increasing the dose of "standard" NSAIDs more than recommended leads to an increase in toxicity, but not efficiency. So the use of NSAIDs in doses exceeding the standards by 1.5 times. increases the risk of developing NSAIDs - gastropathy by 2.8 times. c) An increase in the dose of NSAIDs that predominantly inhibit COX-2 (Movalis, Nise) leads to a loss of their selectivity. d) When taking several NSAIDs at the same time, the risk of developing gastropathy doubles. D. Duration of treatment a) The greatest likelihood of erosions and ulcers of the stomach and duodenum differs in the first month of NP use. b) The development of gastric and duodenal bleeding was noted in 50% of patients using NSAIDs for no more than 7 days. c) The risk of developing gastrointestinal lesions somewhat decreases with prolonged use (after the 4th month) and remains stable over several years of treatment, which is associated with the adaptation process due to an increase in the rate of mucus production and the appearance of young epithelial cells. E. Association of NSAID use with food intake It is well known that the risk of developing gastropathy increases if NSAIDs are taken before meals, which, of course, serves as a reason to recommend taking drugs only after meals. E. Smoking The likelihood of NSAIDs - gastropathy increases in smokers, the risk of gastrointestinal damage increases if there are indications of past exacerbations of PU in the anamnesis. G. Alcohol intake The ulcerogenic effect of NSAIDs on the mucous membrane of the stomach and duodenum is potentiated by alcohol intake, there is a high frequency of ulcer perforation with a combination of factors such as NSAID intake, alcohol abuse, smoking. H. Simultaneous administration of other drugs a) With the simultaneous administration of NSAIDs and anticoagulants, the risk of gastrointestinal bleeding increases, especially in the elderly, with malnutrition, hypoproteemia. b) With the combined use of NSAIDs and GCS, the risk of developing erosive and ulcerative lesions of the gastrointestinal tract increases 10 times. c) Other drugs that increase the risk of developing NSAIDs - gastropathy include: potassium chloride, ACE inhibitors, diuretics. I. Sex More often, erosive and ulcerative gastroduodenal lesions occur in women, especially in old age, which is explained by the increased sensitivity of women to the action of NSAIDs and more frequent, and not always justified, NSAIDs for pain of various origins. t K. Helicobacter pylori The role of H. pylori in the development of NSAIDs - gastropathy is ambiguous. Some researchers answer in the affirmative, others in the negative. 2) So: The algorithm for the prevention of NSAIDs - gastropathy includes: A. Timely detection of patients with a high risk of developing erosive and ulcerative lesions of the gastrointestinal tract. B. Appointment of the least ulcerogenic NSAIDs or selective COX-2 inhibitors (Movalis, Nise). B. Prophylactic prescription of antiulcer drugs. PPI: Omez is prescribed in standard doses - 20 mg / day, lanzap - 30 mg / day, pariet - 10 mg / day. or blockers of H 2 - histamine receptors in standard, and preferably in double doses, or analogues of prostaglandins (mizprostol at a dose of 400-800 mcg / day.) D. Helicobacter pylori eradication therapy. within 7 days according to indications (Omeprazole 20 mg 2 times, Amoxicillin 1000 mg x 2 times Clarithromycin 500 mg x 2 times a day). 3) So, as you saw from the scheme of the algorithm, the most effective drugs in the prevention of NSAIDs - gastropathy are (as in the treatment) PPI Omez or Lanzap, which is confirmed by international studies.
Table 3 Prevention of erosive and ulcerative lesions of the stomach and duodenum caused by NSAIDs after 6 months. treatment. As can be seen from Table 3, according to the OMNION study, it was possible to maintain remission while taking NSAIDs for 6 months. when prescribing Omez in 61% of patients, and when prescribing misoprostol in 48% of patients. However, as you remember, if you consider only the occurrence of erosions, misoprostol was more effective than Omez and placebo, but more effective when taken together. Omez was more effective than ranitidine in preventing NSAID gastropathy and according to the ASTRONAVT study. Table 5 Prevention of erosive and ulcerative lesions of the stomach and duodenum caused by NSAIDs after 6 months. treatment. Remission was noted in 72% of patients while taking Omez and in 59% while taking ranitidine, and, if you remember, in 69% while taking Kvamatel. 4) It should be emphasized that monotherapy with non-absorbable antacids (Maalox, Phospholugel) and sucralfatgel, although it can be used to temporarily reduce the symptoms of dyspepsia, is ineffective in both the treatment and prevention of NSAID gastropathy. Thus, an adequate assessment of risk factors, competent prescription of NSAIDs, as well as the use of preventive measures (Movalis) and treatment of gastrointestinal lesions, especially PPIs (Omez and Lanzap), can significantly improve the safety of treatment of patients with rheumatological diseases and more successfully solve the problem of NSAIDs - gastropathy. .

Loginov A.F., Ph.D.

Institute for Advanced Training of Physicians of the Federal State Institution “National Medical and Surgical Center named after N.N. N.I. Pirogov" Ministry of Health and Social Development of Russia

The term "drug gastropathy", used in the lexicon of modern medicine, is a collective concept that includes dyspeptic syndrome, as well as erosive and ulcerative lesions of the upper gastrointestinal tract (GIT), which develop when taking drugs that have irritating and damaging action on the mucous membranes (CO) of the stomach and less often - the duodenum.

In general, changes when taking such medications can be defined as chemical gastritis (according to the Sydneyclassification), but the morphological changes in SM, ulceration and erosion, determined by light microscopy of biopsy material, cannot be strictly characterized as chemical. Inflammatory changes in the gastric mucosa are detected in almost 100% of cases in patients taking medications with an ulcerogenic effect, and differ only in the severity and frequency of development of erosive and ulcerative defects.SO.

The most widely used group of drugs that have a damaging effect on the mucous membrane of the upper gastrointestinal tract are non-steroidal anti-inflammatory drugs (NSAIDs). The emergence of the term "NSAID-gastropathy" is associated with the identification of changes in the structureSOstomach caused by taking NSAIDs. The second significant factor that must be taken into account by specialists using in medical practice nonsteroidal , is the high frequency of life-threatening complications that develop against the background of erosive and ulcerative lesions of the mucous membrane, primarily bleeding.

The relevance of the problem of prevention and treatment of NSAID-gastropathy is beyond doubt. GroupNSAIDsextremely widely demanded in rheumatology, cardiology clinics, for the treatment of pain and non-specific inflammatory processes. In the last decade, the appointment of NSAIDs to reduce the risk of developing cancer in patients with precancerous processes in the colorectal region, both genetically determined and arising against the background of diseases in this area, has been actively discussed. From year to year, the indications for prescribing are expanding, the number of drugs from the NSAID group that block the "inflammatory" enzyme - cyclic oxygenase type 2 (COX-2) is increasing.

Thus, the prevention and proper treatment of gastroenterological side effects and complications associated with the use of NSAIDs are of great practical importance for specialists in various fields.

Mechanisms of development of NSAID-gastropathy

Inhibition of the production of the enzyme cyclooxygenase (prostaglandin synthetase). COX is an enzyme that catalyzes the synthesis in the body of biologically active substances - prostanoids, the most important of which areprostaglandins, thromboxane and prostacyclin. A group of prostanoids performs the functions of mediators of pain, the implementation of tissue inflammation, and the regulation of adequate platelet lacing. For the gastrointestinal tract, the most important is the functional activity of one of the COX isoenzymes, cyclic oxygenase type 1 (COX-1), physiological, normally constantly present in the tissues of a living organism and ensuring the regulation of the functions described above. The COX-2 isoform is not detected in normal tissues.

The expression of COX-2 is induced by inflammatory mediators (lipopolysaccharides, interleukin-1, tumor necrosis factor alpha) from the cellular substances of the body (macrophages, monocytes, vascular endothelial cells, etc.) and causes all clinical manifestations of inflammatory processes - pain, fever , swelling, dysfunction of the organ.

direct toxic effect. According to the molecular structure, most NSAIDs are weak acids. When taken orally in the gastric contents, they are easily ionized, diffuse into the cells of the gastric mucosa and, upon reaching a certain concentration in epitheliocytes, have a direct damaging effect on intracellular organelles and destroy epitheliocytes.

Systemic toxic effect. NSAIDs, regardless of the form of application (oral, injection, rectal, local) enter the systemic circulation and inhibit the production of mucins, impair microcirculation in the CO, reducing its trophic and reparative properties and thereby reducing the proliferation of epithelial cells of the gastric mucosa, and therefore reducing the protective factorsSO.

The leading role in the development of NSAID-gastropathy is given to the inhibition of COX-1 by reducing the synthesis of protective (cytoprotective) prostaglandins PGE1 and PGE2, which regulate the synthesis of mucins, regional blood flow and secretion of bicarbonates. The "ancestor" of NSAIDs is rightfully considered acetylsalicylic acid (ASA). The popularity and demand for this drug is best evidenced by the numbers: in the 70s of the XX century in the UK, almost 2 thousand tons of ASA were consumed annually (an average of 2 tablets per week for each inhabitant). Back in the early 1990s, in domestic and Western guidelines on rheumatology, ASA was recommended as a first-line drug for analgesic and anti-inflammatory therapy for articular pathology at an initial daily dose of 3-4 g.

The attitude towards ASA drugs, due to the increase in the number of side effects, reflects the famous statement of D. Lawrence and P. Benitt: “... if it were now necessary to administer acetylsalicylic acid, it is unlikely that any of the responsible persons would have the courage to allow its sale to the public” .

According to A.E. Karateev, “... in the hands of an experienced therapist, NSAIDs are a reliable and convenient tool that allows you to quickly alleviate the patient's suffering and improve his quality of life. However, like any tool, these drugs are effective and safe only if they are used correctly. On the contrary, the inept use of NSAIDs without taking into account their pharmacological properties andindividual characteristics of the patient often turns into not only disappointment in their effectiveness, but also the development of dangerous, life-threatening complications. That is why the tactics of correct prescription, dose selection and determination of the duration of administration, control of not only the direct effect, but also possible adverse reactions and complications of NSAIDs, and, if they develop, timely and adequate treatment is the key to success in working with the patient.

Prevention of NSAID gastropathy

Prevention of the negative effect of NSAIDs on the GI tract is currently given a leading place in the treatment of diseases that require the appointment of non-steroidal anti-inflammatory therapy. The most difficult measures, which at the same time provide a good result in reducing the number of side effects, are the refusal to use NSAIDs, minimizing the daily dose of the drug while maintaining an adequate anti-inflammatory and analgesic effect, as well as replacing NSAIDs with a drug of another group, with no damaging effect on the GIT. . Unfortunately, such measures may not be used in all clinical cases.

An effective measure for the prevention of complications is the choice of a safer in relation toSOupper gastrointestinal tract NSAIDs.

So, when taking drugs that equally block COX-1 and COX-2 (non-selective NSAIDs), such as piroxicam and indomethacin, gastropathy develops significantly more often than when using selective drugs that block inflammatory COX-2 to a greater extent and in less "physiological" COX-1, such as voltaren and ibuprofen, meloxicam.

Increasing the dose of selective NSAIDs, unfortunately, makes the risk of NSAID gastropathy equal to that with the use of a non-selective group of drugs. Thus, according to a meta-analysis by D. Henry et al. , the lowest risk of complications (gastrointestinal bleeding and perforation) was found with the use of ibuprofen at low doses, high doses of ibuprofen were associated with the same risk of complications as with non-selective NSAIDs. In a meta-analysis by S.C. Lewis et al. the lowest risk of gastrointestinal bleeding was obtained for ibuprofen (odds ratio (OR) 1.7; 95% confidence interval 1.1-2.5), for diclofenac the OR was 4.9 (3.3-7.1), for indomethacin - 6.0 (3.6-10.0), for naproxen - 9.1 (6.0-13.7), for piroxicam - 13.1 (7.9-21.8) and for ketoprofen - 34.9 (12.7-96.5).

There are also a number of additional factors that increase the risk of developing NSAID-gastropathy and more significant complications (erosions and stomach ulcers, bleeding). These include:

■ age over 65;
■ history of peptic ulcer;
■ large doses and/or concomitant use of several NSAIDs;
■ concomitant use of anticoagulants;
■ concomitant therapy with glucocorticosteroids;
■ duration of NSAID therapy;
■ the presence of a disease requiring long-term use of NSAIDs;
■ female gender;
■ smoking;
■ drinking alcohol;
■ the presence of Helicobacter pylori infection.

The maximum risk of bleeding, regardless of the NSAID taken, occurs in the first week of admission (OR 11.7; 6.5-21.0), decreases with continued use of NSAIDs (5.6; 4.6-7.0) and becomes minimal one week after cancellation (3.2; 2.1-5.1). The use of cytoprotective drugs that enhance the protective propertiesSOThe gastrointestinal tract from damage to NSAIDs is ineffective both for stopping the manifestations of dyspepsia and for reducing the number of side effects of NSAIDs in patients at risk, therefore, at present, the need to prescribe cytoprotectors (misoprostol, etc.) when using NSAIDs is not recognized by all researchers and in practice rarely used.

Issues of drug prevention of side effects and complications when taking NSAIDs are discussed at international forums of specialists. To date, the most effective method is recognized as the simultaneous administration of NSAIDs and cytoprotectors or, more effectively, agents that reduce the acid-producing activity of the stomach (antisecretory drugs).

The use of effective drugs that reduce the production of acid ions and, accordingly, reduce the degree of acid aggression, primarily proton pump inhibitors (PPIs), can significantly reduce the risk of bleeding in the gastrointestinal tract, the development and recurrence of ulcers of the upper gastrointestinal tract, and also reduces the severity of dyspepsia. At the same time, according to A.E. Karateev, the combination of a selective NSAID and PPI is safer than the combination of a non-selective NSAID and PPI. This is confirmed by the results of similarly designed 6-month randomized controlled trials VENUS and PLUTO (n=1378). According to the results obtained, in patients receiving PPIs at a dose of 20 and 40 mg, while taking non-selective NSAIDs, the appearance of ulcers was noted in 7 and 5% of patients, respectively, while in those receiving selective NSAIDs - only 1 and 4% (p<0,05) .

Confirmation of the need for prophylactic administration of acid production inhibitors simultaneously with NSAIDs was also found in the results of the Phase II studies of OMNIUM and ASTRONAUT. Omeprazole at a daily dose of 20 mg was more effective for the secondary prevention of erosive and ulcerative lesions of the upper gastrointestinal tract than misoprostol 400 mg and ranitidine 300 mg. The criteria for effectiveness were: the absence of an ulcer, less than 5 erosions of the gastroduodenalSO, moderate dyspepsia. Possible methods of primary prevention include PPI or misoprostol and eradication. H. pylori. The postulate that eradication H. pylori if it is carried out before the start of the course of NSAIDs, reduces the incidence of ulceration, is included in the provisions of the Third Maastricht Consensus.

Treatment of erosive and ulcerative lesions caused by NSAIDs

The first of the most significant international consensus on the use of NSAIDs based on evidence-based medicine took place on the island of Sardinia in 2001. are the drugs of choice for healing ulcers caused by NSAIDs, especially gastric ulcers. This conclusion is based on the results of several clinical studies, primarily OMNIUM (comparison of the effectiveness of omeprazole and misoprostol in the treatment of ulcers caused by NSAIDs) and ASTRONAUT (comparison of the effectiveness of omeprazole and ranitidine). These studies were carried out according to the same design in two phases: treatment - with the determination of effectiveness at the 4th, 8th and 16th weeks, and the secondary prevention phase (6 months). The studies included patients taking chronic NSAIDs (with rheumatoid arthritis or osteoarthritis), with endoscopically confirmed gastric ulcer, duodenal ulcer and/or erosions (at least 10 gastroduodenal erosions).SO).

The results of the effectiveness of omeprazole in the healing of erosive and ulcerative lesions of the stomach and duodenum (duodenal ulcer) caused by NSAIDs, compared with misoprostol, are presented in table 1.

Omeprazole (at a dose of 20 mg) was found to be significantly more effective in scarring gastric ulcers than misoprostol (p=0.004). It showed the greatest advantage in scarring of duodenal ulcers (p<0,001).

It is interesting to note that in the healing of gastroduodenal erosions, a more pronounced effect was exerted by the synthetic analogue of prostaglandin misoprostol (p=0.01). At the same time, when using it, diarrhea was detected in 11% of patients, 8.9% of patients complained of abdominal pain, 16.9% prematurely completed the drug. Omeprazole at doses of 20 mg and 40 mg was more effective than ranitidine in healing all of these lesions.

In these studies, the first of the modern drugs of the antisecretory drugs group, PPI-omeprazole, was used. To date, doctors have at their disposal other representatives of this class of acid production inhibitors (lansoprazole, pantoprazole, esomeprazole, rabeprazole). The action of this group of drugs is based on the mechanism of blocking transmembrane proton transfer, carried out by a specific enzyme - H + /K + -dependent ATPase or "proton pump". Reliable inhibition of the entry of hydrogen ions into the lumen of the stomach provides a double effect: conditions are created for adequate CO reparation by reducing the aggressive properties of gastric contents, and changing the pH of gastric juice to pH 5-6 reduces the activation of pepsinogen into pepsin to 20-30% of the initial values, which reduces the proteolytic properties of gastric juice, and therefore reduces the risk of autolysis of a blood clot (thrombus), which reduces the risk of recurrent bleeding due to the lysis of a thrombus formed in a bleeding vessel.

The peculiarity of all PPIs is that the active form of these compounds - sulfenamide, which is a cation - does not pass through cell membranes, remains inside the tubules and does not have side effects. The rate of activation and efficiency of PPI use depend on the pH of the medium and the value of the dissociation constant (pKa) for each drug. The optimum pH for all PPIs is between 1.0 and 2.0.

PPIs are the most powerful blockers of gastric secretion today. They inhibit the production of acid by almost 100%, and due to the almost complete irreversibility of fixation with the enzyme, the effect persists for several days, and the restoration of acid production occurs after 4-5 days, and therefore the rebound phenomenon is not typical for them.

Table 1. Healing of NSAID-induced erosive and ulcerative lesions of the stomach and duodenum after 8 weeks of treatment according to the OMNIUM and ASTRONAUT studies

A drug	Healing of erosive and ulcerative lesions
	stomach ulcer	duodenal ulcer	erosion
OMNIUM Study
Omeprazole 20 mg
Omeprazole 40 mg
Omeprazole 800 mg
ASTRONAUT study
Omeprazole 20 mg
Omeprazole 40 mg
Omeprazole 800 mg

PPIs, especially the latest generation drugs, selectively bind to two cysteine ​​molecules of the proton channel and have a stronger effect on H + /K + -ATPase, almost without affecting cytochrome P450 and without interacting with other drugs, which allows them to be used in various therapeutic combinations.

The use of modern PPIs is rarely accompanied by side effects. At the same time, with their long-term use, moderate hypergastrinemia develops with a slight increase in the number of enterochromaffin-like (ECL) cells, which is due to the reaction of G-cells of the CO from the stomach and duodenum in response to an increase in pH in the antrum of the stomach.

Clinical features of NSAID-gastropathy: a clinical picture with a minimum number of complaints, more often of a dyspeptic nature, lack of expression or complete absence of a signal pain syndrome due to the analgesic effect of NSAIDs; the presence of a drug load associated with the treatment of the underlying disease (NSAIDs or NSAIDs in combination with drugs of other groups) force the doctor to more carefully choose both preventive and therapeutic agents in the event of dyspepsia or erosive and ulcerative lesions of the gastrointestinal tract. WITHtaking into account recent research, all these requirements are met by proton pump inhibitors. Considering the high efficiency of PPIs in acid-dependent diseases, the physician should opt for one of the types of H + /K + -ATPase inhibitors. The decisive factor of choice is not the rate of blocking the transmembrane transport of hydrogen ions and early relief of pain (as a rule, it is not pronounced or absent), but gradual and long-term and intense inhibition of acid production.

Of the PPIs present on the market, pantoprazole (Controloc) possesses the listed qualities, the bioavailability of which is 77%, plasma protein binding is 98%, and the maximum plasma concentration of the drug is reached 2-4 hours after administration. Food intake, as well as the route of administration of the drug (oral or intravenous) do not affect its pharmacokinetics.

Compared to other PPIs, Controloc has little effect on the activity of the cytochrome P450 system, which clearly reduces its effect on the metabolic elimination of concomitant drugs compared to omeprazole or lansoprazole. In the treatment of erosive and ulcerative lesions while taking NSAIDs, pantoprazole is recommended to be used at a dose of 40 mg / day, and more effective suppression of gastric secretion occurs when taking the drug in the morning.

The use of pantoprazole is also indicated for the purpose of long-term maintenance prevention of ulcerative lesions of the upper gastrointestinal tract. According to H. Heinze et al. , the use of pantoprazole for the treatment of patients with peptic ulcer for 10 years or more was not accompanied by relapses of the disease and significant side effects, which fully complies with the requirements for a drug for the prevention and treatment of NSAID-gastropathy.

With prolonged use of Controloc, an increase in the concentration of gastrin in the blood occurs. According to some authors, a year after treatment, the content of gastrin increases on average 3 times, according to others - 2 times, the plateau is reached by the 9th month of taking the drug. The content of ECL cells during the year of treatment increases slightly - from 0.19 to 0.24%. These data suggest that pantoprazole Controloc is as safe as other PPIs.

At the same time, Controloc, unlike omeprazole and esomeprazole, does not accumulate in the body after taking repeated doses. Linear pharmacokinetics ensures the effectiveness of the drug throughout the course of treatment, starting from the first day of its administration. Pharmacokinetic parameters (AUC - 5.35 mg h / l, maximum plasma concentration - 5.26 mg / l, half-life - 1.11 h) after intravenous administration of Controloc at a dose of 30 mg / day for 5 days were comparable to those obtained after its single intravenous administration.

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