Modern drugs for the treatment of ulcers
Peptic ulcer of the stomach and duodenum still remains one of the most common gastrointestinal problems. In recent years, approaches to the treatment of ulcers have gradually changed due to outstanding achievements in microbiology, physiology and anatomy.
What is an ulcer
The morphological substrate - an ulcer - is a defect in the mucous membrane, which is formed under the aggressive influence of gastric contents against the background of a reduced ability of the mucous membrane to restore and protect itself. All areas of therapy come down to eliminating these factors of aggression and increasing the protective properties of the mucosa.
Proton pump inhibitors and their effects
In the treatment of ulcers, the problem of high acidity comes first, and ways to solve this problem were developed decades ago, after the discovery in 1973 of a special protein “pump” - a proton pump that supplies hydrogen protons for the formation of hydrochloric acid in the stomach.
Treatment of ulcer bleeding and prevention of relapse: a therapist’s view
I.V. MAYEV
1, corresponding member.
RAMS, Doctor of Medical Sciences, Professor, A.Yu.
GONCHARENKO 1, Ph.D., Associate Professor,
D.T.
DICHEVA 1, Ph.D., Associate Professor,
D.N. ANDREEV
1,
V.S.
SHVYDKO 2, Ph.D.,
T.A.
BURAGINA 1,2 1
Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Budgetary Educational Institution of Higher Professional Education "MGMSU named after.
A.I. Evdokimov" of the Ministry of Health of Russia 2
Federal Clinical Institution "Main Clinical Hospital of the Ministry of Internal Affairs of Russia" Gastroduodenal bleeding can complicate various diseases of the esophagus, stomach, duodenum, hepatopancreatobiliary system, and how oriented the clinician is in modern diagnostic methods and adequate choice of treatment tactics ultimately depends life of the patient [1].
According to modern data, bleeding from the upper gastrointestinal tract (GIT) occupies a dominant place in the structure of all gastroduodenal bleeding and accounts for 80–90% of cases [2]. The annual incidence among the adult population ranges from 48 to 160 cases per year per 100 thousand people [3, 4]. The urgency of the problem is emphasized by the mortality rate, which ranges from 6 to 14%, and in the group of patients with severe bleeding reaches 50% [2, 3, 5].
Among the causes of bleeding from the upper gastrointestinal tract, two large groups are distinguished: bleeding of an ulcerative nature (44–49% of cases) and bleeding of a non-ulcerative nature (51–56% of cases) (Table 1) [1].
It is worth noting that today in the world peptic ulcer of the stomach and duodenum is one of the most common diseases (from 5 to 15%, on average 7–10% of the adult population) and ranks second after coronary heart disease [6, 7]. In the Russian Federation, the incidence of gastric and duodenal ulcers was 157.6 per 100 thousand population [7, 8].
Recently, foreign literature has often noted a tendency towards a decrease in the prevalence of gastric and duodenal ulcers in Western Europe and North America, but this process does not correlate with the frequency of ulcer bleeding [3, 5]. At the same time, despite the effectiveness of modern therapy, the number of patients with ulcer bleeding is increasing [9]. According to Russian authors, over the past 8–10 years, the number of patients with ulcer bleeding has increased 1.5 times [1].
It appears that the reasons for the high incidence of ulcer bleeding in Europe and North America and Russia are different. Thus, in Russia, the high frequency of ulcer bleeding is most likely associated with the low social level of the population, which in turn causes a high prevalence of major risk factors, such as smoking, infection with Helicobacter pylori (H. pylori), etc. [10, 11] . In contrast, consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased rapidly in Western European and North American populations in recent years [5]. Taking NSAIDs increases the risk of developing erosive and ulcerative lesions of the mucous membrane by 3–5 times, and the risk of bleeding and perforation by 8 times [12].
The mechanism of bleeding formation in gastric and duodenal ulcers is caused by a deep ulcerative defect, when the bottom of the ulcer reaches the wall of the blood vessel. Thinning and necrosis of the vascular wall occurs indirectly, initiating bleeding. Thus, it has been shown that the source of bleeding of an ulcerative nature can be both arrosive vessels of various diameters located at the bottom of the ulcer, and the edges of the ulcer crater themselves, bleeding diffusely due to inflammatory-destructive changes in the wall of the affected organ. It is worth noting that most often massive and life-threatening bleeding comes from callous ulcers of the lesser curvature of the stomach and the posteromedial part of the duodenal bulb, which is associated with the peculiarities of the blood supply to these zones [1, 2, 13].
The main risk factors for bleeding of a ulcerative nature include old age, as well as the use of NSAIDs, anticoagulants and glucocorticoids [5]. In men, gastroduodenal bleeding occurs 2.5–3 times more often than in women [3].
The severity of clinical symptoms reflects the patient’s individual reaction to blood loss and is determined both by the intensity and massiveness of the bleeding itself, and by the initial state of the body and its compensatory capabilities. The most striking clinical manifestations are observed with massive bleeding with a loss of about 25% of the blood volume within a fairly short time interval (minutes to hours) [1]. In such cases, the clinical picture corresponds to hemorrhagic (hypovolemic) shock and is manifested by hypotension, tachycardia, marbling of the skin, and a decrease in central venous pressure.
Symptom complexes of acute gastroduodenal ulcerative bleeding can be divided into general, characteristic of any blood loss, and specific, characteristic of intraluminal bleeding.
General symptoms of blood loss are varied and include severe general weakness, dizziness, a feeling of darkening in the eyes, palpitations, and shortness of breath. With massive bleeding, loss of consciousness may occur due to increasing circulatory hypoxia.
Symptoms that characterize intraluminal bleeding include vomiting blood (hematemesis) and black, tarry stools (melena). It is believed that for such characteristic signs of intraluminal bleeding to appear, a loss of about 500 ml of shed blood is necessary. Vomiting of blood is usually always associated with melena. A characteristic sign of gastric bleeding is vomit in the form of coffee grounds, which is determined by the formation of hematin chloride during the interaction of blood hemoglobin with hydrochloric acid of the stomach. Melena appears no earlier than 8 hours after the start of bleeding. It is worth noting that with massive bleeding (in the case of intraluminal release of more than 1500 ml of blood), melena does not form, and the release of slightly changed scarlet blood (hematochezia) may be observed from the rectum [2, 13, 14].
Depending on the volume of blood loss and BCC deficiency, 3 degrees of severity of acute gastroduodenal bleeding are distinguished (Table 2). To calculate BCC, the Algover-Burri shock index (1967), determined by the ratio of pulse rate and systolic blood pressure, is often used. With an index of 0.8 or less, the volume of blood loss is equal to 10% of the bcc, with 1.3–1.4 – 30%, with 1.5 and above – 50% of the bcc or more [2].
In the diagnosis of gastroduodenal bleeding, the patient's medical history is of great importance. Taking into account the fact that in the prevailing number of patients bleeding occurs against the background of an exacerbation of peptic ulcer disease, it is possible to identify clinical manifestations characteristic of this disease (the presence of “hungry” pain, often accompanied by heartburn, relieved after taking antacids and proton pump inhibitors (PPIs), often associated with seasonal nature) [1, 6, 13].
Instrumental research methods are aimed at identifying the exact location of the bleeding area. Today, the leading instrumental method for diagnosing gastroduodenal bleeding is emergency esophagogastroduodenoscopy (EGD) [1–3, 10, 14]. This method makes it possible to most accurately verify the source and nature of bleeding, as well as assess the risk of early relapses. Also, the endoscopic picture underlies the classification of the activity of gastroduodenal ulcerative bleeding (according to JA Forrest, 1974) [15]. In accordance with this classification, it is customary to distinguish between active (Forrest Ia/Ib) and ongoing (Forrest II/III) bleeding (Table 3). The use of this classification allows us to unify the description of a bleeding gastroduodenal ulcer, and therefore avoid discrepancies and unambiguously interpret the intensity of bleeding and its source. Based on the above indicators, the endoscopist assesses the potential for recurrent bleeding.
Methods of conservative hemostasis are aimed at creating conditions for the formation, retraction and organization of a thrombus in the lumen of a bleeding vessel, preventing lysis and dislocation of the thrombus, and realizing the tissue reparative potential of the gastric and duodenal wall in the periulcerous zone [16]. In some cases, combined endoscopic hemostasis is chosen, combining the injection of adrenaline and an alcohol-novocaine mixture into the edges of the ulcer with argon plasma coagulation or diathermocoagulation. However, the success of therapy for gastroduodenal bleeding lies in the combination of endoscopic hemostasis with adequate drug therapy, the basic drugs of which are antisecretory drugs [2, 10, 14, 16].
The basis for prescribing antisecretory drugs that inhibit the production of hydrochloric acid is a decrease in the activity of pepsin or its inactivation when the intragastric pH increases >4 units, which leads to a decrease in the aggressive properties of gastric juice due to impaired activation of pepsin, reduces the reverse diffusion of hydrogen ions and their damaging effect on gastric mucosa. In addition, under conditions when pH (6.0–7.0 units), the contents of the stomach shift to the alkaline side, the lysis of fresh blood clots is blocked, which allows for complete vascular-platelet hemostasis [17]. Because of this, it is important to choose antisecretory drugs that ensure the longest possible alkalization in the gastric cavity. These antisecretory drugs include the PPI class, while the use of the older class of histamine H2 receptor blockers is not currently recommended [16, 18].
The main positions on the use of PPIs as part of drug therapy for gastroduodenal bleeding were regulated by the international consensus on the management of patients with non-variceal bleeding from the upper gastrointestinal tract in 2010 [18].
According to provision A8 of the above-mentioned document, the infusion of PPIs before the initial endoscopic examination is fully justified, which reduces the frequency of the need to use endoscopic methods of hemostasis (level of evidence 1b) [18]. It is important to emphasize that such tactics should in no case be considered as an excuse for delaying emergency endoscopic examination [19].
Statement C3 states that after successful endoscopic hemostasis, an intravenous bolus followed by a continuous infusion of PPI is recommended. This approach reduces the risk of rebleeding and therefore mortality in this group of patients (level of evidence: 1a) [18].
In a large Cochrane meta-analysis of 5,792 patients, high-dose intravenous PPI therapy (80 mg bolus and 8 mg per hour continuous infusion) resulted in a reduction in rebleeding rates (RR 0.43, CI 0.27 to 0.67) , surgical interventions (RR – 0.60 CI 0.31–0.96) and mortality (RR – 0.57, CI 0.34–0.96). And low doses of PPI, both intravenously and orally, reduced the incidence of rebleeding, but did not reduce the mortality rate [20].
According to provision B6, in the case of a thrombus-clot tightly fixed to the ulcer crater, endoscopic hemostasis may not be performed, since intensive intravenous high-dose PPI therapy may be sufficient (evidence level 2b) [18]. Thus, according to a meta-analysis by Laine L. et al. (2009), who summarized data from 5 randomized controlled trials (189 patients), did not find a significant advantage of endoscopic treatment compared with medication (OR – 0.31, CI: 0.06–1.77) [21].
In position C4, it is recommended to continue treatment with daily single doses of PPI orally even after the patient is discharged from the hospital. The duration of such treatment is determined by the etiology of the disease (level of evidence: 1c) [18]. Thus, patients requiring treatment with NSAIDs may require long-term secondary prevention [22]. A number of experts suggest twice-daily dosing of PPIs for convalescents, which helps prevent acid breakthroughs during treatment [23]. Important characteristics when choosing a PPI are the range of dosage forms (intravenous, oral or nasogastric tube) and pharmacokinetic properties that allow its use in patients with multiple organ dysfunction (renal and hepatic). Intravenous forms exist for omeprazole, pantoprazole, esomeprazole and lansoprazole. Pantoprazole (the drug Controloc), starting from the first dose, has high bioavailability (77%), due to which it quickly exerts a pronounced suppression of hydrochloric acid secretion. Intravenous pantoprazole 80 mg followed by infusion over 24 hours at a rate of 8 mg/hour maintained intragastric pH above 4 for 99% of the 24-hour period and above 6 for 84% of that time in 8 healthy volunteers. . After endoscopic examination and hemostasis, intravenous administration of pantoprazole at a dose of 80 mg followed by continuous infusion at a rate of 8 mg/h for 3 days in 14 patients with gastric and duodenal ulcers complicated by bleeding increased the median intragastric pH to 6.3 (monitoring – more than 48 hours). In this study, the median relative time the pH was above 4, 5, and 6 was 97.5; 90.5 and 64.3% respectively.
Controloc has constant, linear, predictable pharmacokinetics. When doubling the dose of PPIs, which have nonlinear pharmacokinetics, their serum concentrations will be either lower or higher than expected, i.e., they are unpredictable. This may affect the safety of using the drug. In elderly patients or with severe renal failure (creatinine clearance - 0.48–14.7 ml/min) there is no need to adjust the dose of pantoprazole. After its intravenous administration at a dose of 30 mg/day for 5 days in patients with hepatic impairment (Child-Pugh class A and B), the AUC and half-life values increased 5-6 times compared with those in healthy volunteers. Pantoprazole is the only PPI drug that is not involved in known metabolic pathways of interaction with other drugs. Compared to other PPIs, pantoprazole, due to the specificity of phases I and II of biotransformation, has a lesser effect on the cytochrome P-450 system. In particular, it inhibits the cytochrome P-450 system to a lesser extent than omeprazole or lansoprazole. Due to the severity of the condition, a large number of drugs are being actively used with antisecretory drugs. The most serious consequences of polypharmacy are an increased risk of adverse reactions and drug interactions. So, when taking two drugs, the potential risk of their interaction is 6%, and when taking five – 50%. To prevent these adverse effects (regardless of the number of medications taken at the same time), it is preferable to take a drug that has the potential to interact poorly with other medications. In particular, pantoprazole does not interact clinically with drugs used in intensive care such as antacids, caffeine, metoprolol, theophylline, amoxicillin, clarithromycin, diclofenac, naproxen, diazepam, carbamazepine, digoxin, nifedepine, warfarin, cyclosporine, tacrolimus and etc.
The dosage regimen of the drug - bolus or intravenous infusion - is determined individually and depends on the level of risk factors for the development of stress damage to the gastrointestinal tract. According to the results of a number of meta-analyses of clinical studies, PPI therapy in critically ill patients for the prevention of erosive and ulcerative lesions of the upper gastrointestinal tract leads to a reduction in the need for transfusion therapy, the duration of hospitalization and the incidence and relapse of the gastrointestinal tract.
Experts who participated in the development of international consensus recommendations for the management of patients with nonvariceal upper gastrointestinal bleeding pay great attention to the role of H. pylori eradication. The prevalence of this infection in patients with upper gastrointestinal bleeding is quite high and varies from 43 to 56% [24, 25].
Statement D5 states that all patients who have suffered ulcer bleeding should be tested for the presence of H. pylori and, if detected, receive eradication therapy with mandatory confirmation of the success of anti-Helicobacter pylori treatment (evidence level 2a) [18].
In accordance with the Maastricht IV consensus (2010), regulating the standards for diagnosis and treatment of H. pylori infection, in regions with low H. pylori resistance to clarithromycin (less than 20%), triple therapy is regulated as first-line eradication therapy, including PPI, clarithromycin and amoxicillin. In regions with high resistance of H. pylori to clarithromycin (more than 20%), quadruple therapy with bismuth preparations (PPI + metronidazole + tetracycline + bismuth tripotassium dicitrate) or sequential eradication therapy (first 5 days - PPI + amoxicillin, the next 5 days – PPI + clarithromycin + tinidazole/metronidazole) [26, 27].
In case of failure of eradication with first-line treatment regimens, the expert council of the Maastricht IV consensus regulates the transition to second-line regimens. Thus, quadruple therapy based on bismuth preparations is a priority for regions with a low prevalence of resistant strains of H. pylori to clarithromycin, and triple therapy with levofloxacin (PPI + amoxicillin + levofloxacin) is proposed as an alternative. As for regions with high resistance of H. pylori strains to clarithromycin, according to the Maastricht IV consensus, the second-line therapy, if first-line quadruple therapy is ineffective, is triple therapy with levofloxacin (PPI + amoxicillin + levofloxacin) [26, 27].
Returning to the therapeutic aspects of the treatment of gastroduodenal bleeding, one cannot fail to mention provision D6 of the international consensus on the management of patients with nonvariceal upper gastrointestinal bleeding, according to which H. pylori - a negative result should be reconfirmed after the bleeding has stopped (evidence level 1b) [18] . In the setting of acute bleeding, test results for H. pylori may be falsely negative, although the biological mechanisms in this case are not well understood. The likely mechanism for this phenomenon may be related to the buffering effect of blood, since in a more alkaline environment false negative results are obtained more often [28]. A systematic review of 23 studies conducted for consensus review showed a high positive predictive value (0.85–0.99) of diagnostic tests for H. pylori infection (including serology, histology, urea breath test, rapid urease test, antigen test). stool and culture) with a low predictive value of these tests (0.45–0.75) in conditions of gastroduodenal bleeding. In this group of patients, false-negative results were 25–55% [29].
The development of standardized approaches to the management of patients with non-variceal gastroduodenal bleeding aims to reduce the rate of rebleeding, surgical interventions and mortality. A consensus statement on the management of patients with nonvariceal upper gastrointestinal bleeding was developed by a reputable community of experts based on the analysis of extensive statistical data. The basis for success is timely examination of the patient and initiation of adequate drug treatment, discussed above.
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Clinical picture of peptic ulcer
The most consistent and important symptom of peptic ulcer disease is pain. Pain in peptic ulcer disease has a clearly defined rhythm (time of occurrence and connection with food intake), and seasonality of exacerbations.
Based on the time of occurrence and their connection with food intake, pain is distinguished between early and late, night and “hungry”. Early pain occurs 0.5–1 hour after eating, lasts 1.5–2 hours and decreases as gastric contents are evacuated. Such pain is more typical for gastric ulcer in the upper part.
Late pain appears 1.5–2 hours after eating, night pain occurs at night, and “hungry pain” occurs several hours after eating and stops after eating. Late, night and “hungry” pains are more typical for the localization of an ulcer in the antrum of the stomach or duodenal ulcer.
The nature and intensity of pain may vary (dull, aching, burning, cutting, cramping). The localization of pain in peptic ulcer disease is different and depends on the location of the ulcer: with an ulcer on the lesser curvature of the stomach, pain often occurs in the epigastric region, with duodenal ulcers - in the epigastric region to the right of the midline. With ulcers of the cardial part of the stomach, pain can be behind the sternum or in the heart area; in this case, it is important to differentiate peptic ulcer disease from angina pectoris or myocardial infarction. Pain often occurs after taking antacids, milk, food, and even after vomiting.
In addition to pain, the typical clinical picture of peptic ulcer disease includes various dyspeptic symptoms.
Heartburn is one of the early and frequent symptoms characteristic of peptic ulcer disease. Heartburn can occur at the same time after eating as pain. It often precedes the onset of pain, and subsequently is often combined with pain. These two symptoms are closely related, and some patients have difficulty distinguishing between them. In later stages of the disease, heartburn may disappear. But sometimes it can be the only subjective manifestation of a peptic ulcer.
Belching is a fairly common, but not specific symptom of peptic ulcer disease. The most typical belching is sour. The appearance of belching is associated with impaired evacuation of gastric contents due to prolonged spasm and severe inflammatory edema of the pylorus or duodenal bulb. It should also be remembered that belching is characteristic of a diaphragmatic hernia.
Nausea and vomiting are dyspeptic symptoms characteristic of exacerbation of peptic ulcer disease. Nausea is often accompanied by vomiting, although vomiting can occur without preceding nausea.
Vomiting in patients with peptic ulcer disease often has some specific features: firstly, it occurs at the height of pain, being, as it were, the culmination of pain; secondly, it brings significant relief. Vomit, as a rule, has an acidic reaction with an admixture of recently eaten food. Vomiting can also occur on an empty stomach.
Appetite in case of peptic ulcer is usually preserved or even increased (the so-called painful feeling of hunger). Decreased appetite is possible with severe pain syndrome; fear of eating may occur due to the possibility of pain occurring or increasing. Decreased appetite and fear of food can lead to significant weight loss for the patient.
Constipation is observed in half of patients with peptic ulcer disease, especially during exacerbation. Constipation in peptic ulcer disease is caused by a number of reasons: spastic contraction of the colon, a gentle diet, poor coarse fiber and the resulting lack of intestinal stimulation, limitation of physical activity, and the use of antacids (Almagel, etc.).
Symptoms depend on the location of the ulcer and the age of the patient . In some cases there may be no pain (painless ulcers). In these cases, ulcers are discovered when complications develop (ulcer bleeding, ulcer perforation - breakthrough of the ulcer wall into the abdominal cavity, penetration of the ulcer). Only about half of people with duodenal ulcers (duodenal ulcers) have typical symptoms. In children, the elderly, and patients taking certain medications, symptoms may be atypical or absent altogether.
