Bismuth tripotassium dicitrate. Reviews, instructions, names, analogues, price

• May 6, 2020
• Gastroenterology
• Ulyana Romanova

“Bismuth tripotassium dicitrate” is a very common antiulcer agent in medical practice, which has an antiseptic and astringent effect. What conditions is it prescribed to treat? How does it affect the body? Are there any contraindications? You will find answers to the most important questions regarding this medication below.

Chemical composition of bismuth tripotassium dicitrate

According to its chemical origin, the substance in question is a colloidal bismuth subcitrate, which is highly resistant to unfavorable acidic environments. Tripotassium bismuth creates a protective coating on the surface of erosive and ulcerative lesions by stimulating the production of prostaglandins and protective mucus.

The medicinal compound belongs to the group of heavy non-toxic metals. The safety of chemical compositions with bismuth can be explained by its lack of water-soluble properties.

All compounds with bismuth have minimal bioavailability because they do not interact with biological fluids. Such drugs do not enter the bloodstream, due to which they produce a powerful therapeutic effect in areas of local damage.

The absence of toxic trace elements in bismuth preparations is their undoubted advantage. Treatment of ulcerative pathologies of the gastrointestinal tract with medications containing bismuth compounds is well tolerated in most cases.

Properties

Bismuth tripotassium dicitrate, reviews of which confirm its effectiveness, belongs to the category of antiulcer bactericidal drugs. The substance demonstrates antimicrobial properties against the pathogen Helicobacter pylori.

Bismuth compounds have a number of medicinal properties. Such drugs stop the inflammatory process and have an astringent effect. The therapeutic effect is achieved due to the formation of a group of substances that are insoluble in the highly acidic environment of the stomach and have protein substrates.

A series of chemical reactions leads to the formation of a protective film coating on the surface of ulcerative-erosive formations.

Thanks to the action of bismuth, the body increases the production of prostaglandin E and normalizes the process of its synthesis.

The intensity of secretion of protective mucus and the immunity of the mucous membrane of internal organs to the influence of enzyme compounds, gastric juice, and bile depend on the concentration of this lipid substance. In this regard, the use of bismuth-based medications can accelerate the generalized restoration of the epidermal surface.

Bismuth preparations in medical practice

Bismuth is a chemical element of the 15th group of the sixth period of the periodic table of chemical elements of D. I. Mendeleev; has atomic number 83, and under normal conditions is a shiny silvery metal with a pinkish tint. Actually, the element was introduced into chemical nomenclature as “bismuth” in 1819 by the Swedish chemist J. Berzelius. Without being malleable or malleable, bismuth is easily crushed into powder. Bismuth has been known since ancient times (the first mention of it in chemical literature dates back to the 15th century), but for a long time it was considered a type of tin, lead or antimony. The idea of ​​bismuth as an independent chemical element emerged only in the 18th century, after its chemical identity was established in 1739 by the German chemist I. Pott [1, 2].

The biological role of bismuth has been poorly studied; scientists suggest that this element induces the synthesis of low molecular weight proteins, takes part in ossification processes, and forms intracellular inclusions in the epithelium of the renal tubules. The current level of knowledge does not allow us to speak definitely about any physiological role of bismuth in the human body. Its intake into the body with water or food is insignificant, since the absorption of bismuth entering the gastrointestinal tract is extremely small and amounts to about 5%. The daily intake of bismuth into the body from food is 0.02 mg, and from air - 0.00001 mg.

It seems much more likely that bismuth will enter the body with medications when taken orally or through the skin (for external use). In total, the human body enters the human body with food, as well as with air and water, in the amount of 5–20 mcg/day. After absorption, bismuth is found in the blood in the form of compounds with proteins, and also penetrates into red blood cells. Bismuth is distributed relatively evenly between organs and tissues. Some accumulation of bismuth may be observed in the liver, kidneys (up to 1 μg/g), spleen and bones. Bismuth is also found in the brain. Bismuth belongs to the category of heavy metals; it is a moderately toxic element. A number of sources even call bismuth “the most harmless” of all heavy metals. Being very close in its properties to lead, bismuth is much less toxic. In this regard, environmentalists are advocating for the gradual replacement of lead in industrial and production processes with bismuth. Occupational poisoning or skin diseases are almost never reported when working with bismuth; the carcinogenicity of this metal has also not been established. Usually, even huge doses of bismuth taken orally do not cause poisoning, which is explained by the difficulty of absorption of bismuth compounds [2].

Leukocytes are responsible for transporting bismuth to various organs in the body. Captured by leukocytes and carried by the blood and lymph throughout the body, bismuth accumulates in the spleen, central nervous system and excretory organs, which include the kidneys, liver, intestines, and salivary glands. Its bioavailability is very low - 0.16–1.5% of the dose taken. The average concentration of bismuth in the blood after a course of treatment does not exceed 3–58 mcg/l. Traces of this element have been found in sweat, tears and breast milk. Resorbed bismuth is excreted in the urine. Long-term use of bismuth preparations in large doses can cause symptoms of “bismuth” encephalopathy (especially in patients with impaired renal function). Based on an analysis of 945 clinical cases, it was proven that side effects occur only when very high doses of drugs (up to 20 g/day) are used for a long time (2–20 years or more) [3].

Bismuth is mentioned in the works of many authors of books of the 15th–17th centuries, in particular by Valentine and Paracelsus. 150 years ago, some bismuth compounds were used as a disinfectant, drying agent, astringent and antiseptic. Bismuth is an element that, like silver, has antimicrobial properties. The independent use of bismuth for therapeutic purposes is difficult due to a number of undesirable effects, therefore, optimization of the use of bismuth as an antibacterial agent is associated with the development of appropriate forms and complexes (salts) that allow efficient transport of this ion to the immediate site of action. The therapeutic activity of bismuth compounds has been known for a long time and has been described for various bismuth salts, and its oral and parenteral administration was intended for the treatment of a number of diseases, such as syphilis, Vincent's angina and amoebiasis dysentery [4]. When bismuth salts became widely in demand, small-scale production of their preparations in the form of mixtures was established. Bismuth ammonium citrate (BAC), sometimes bismuth tartrate, known as “bismuth ammonium citrate with pepsin,” became widely known in Great Britain in the first half of the 20th century. Bismuth preparations have been described in various articles of the British Pharmaceutical Codex since the 1929 edition.

Around the same time, bismuth preparations were developed in Germany, in which protein or peptide hydrolysates and their fractions were used as a complexing agent (German Pat. No. 117 269, German Pat. No. 101 683, German Pat. No. 202 955). But they had obvious disadvantages - the unregulated release of bismuth ions (determined by the pH values ​​of the stomach) were adsorbed in the upper gastrointestinal tract, forming compounds that caused the penetration of bismuth ions into the internal environments of the body. These shortcomings contributed to the search for new effective and safe bismuth derivatives.

Bismuth compounds have an antispirochetal effect, and the mechanism of their action is that bismuth ions, penetrating into spirochetes, bind the sulfhydryl groups (SH) of their enzymes, leading to disruption of the vital functions and death of syphilis pathogens. Such drugs are administered intramuscularly, since when taken orally, bismuth-containing compounds are practically not absorbed from the digestive tract. However, with parenteral intake of bismuth into the body, there is a danger of damage to those organs in which bismuth ions accumulate. The toxic and lethal doses of the eighty-third element for humans have not been determined. Chronic intake of bismuth in quantities of 1–1.5 grams per day is considered dangerous. The importance of bismuth salts in medicine increases over time. Many drugs have been developed based on bismuth gallate, tartrate, carbonate, tribromophenolate, subcitrate and subsalicylate. In medical practice, drugs such as Vikalin, Vikair, Vikram, Neo-Anuzol, Bismuth ointment, Dermatol, Xeroform, Pentabismol, Bismutogvi, De-Nol, Novobismol and others are used.

Previous studies have determined that combining bismuth with thiol (-SH, sulfhydryl) compounds, such as bismuth ethanedithiol, improves the antimicrobial activity of bismuth compared to other bismuth salts. The search for new optimized bismuth transmitters continues, as evidenced by a recent patent for an invention [5], describing the preparation and use of a bismuth-thiol composition as an effective antibacterial agent.

Today in Russia, gastroenterologists most widely use colloidal bismuth subcitrate, or, as it is also called, bismuth tripotassium dicitrate (BTD). The discovery of Helicobacter pylori (H. pylori) in 1983 by Australians J. Warren and B. Marshall revolutionized the treatment of peptic ulcers [6], it renewed interest in bismuth compounds, since it was found that bismuth salts effectively suppress the growth of H. pylori in combination with antibiotics or in combination with antibiotics and acid-suppressive drugs [7, 8]. The first randomized controlled trial (RCT) using bismuth in anti-Helicobacter therapy found that bismuth was more effective than erythromycin monotherapy [9]. Another RCT compared the effectiveness of colloidal bismuth subcitrate versus cimetidine in H. pylori-positive duodenal ulcer over a 6-week period, with bismuth successfully eradicating H. pylori in 50% of patients [10]. The next RCT evaluated the combined use of colloidal bismuth subcitrate and cimetidine, alone or in combination with tinidazole, and found that colloidal bismuth subcitrate and tinidazole achieved H. pylori eradication in almost 75% of patients [11]. With the addition of a second antibiotic, tetracycline or amoxicillin, the eradication rate in later RCTs exceeded 80% [12–14]. However, some problems with bismuth-based triple therapy were identified, including the large number of pills patients were required to take, the duration of therapy, and side effects such as taste changes, nausea, and diarrhea. Systematic review and meta-analysis by A. Ford et al. There is strong evidence that bismuth compounds, used either alone or in combination with antibiotics and proton pump inhibitors (PPIs) to eradicate H. pylori, are safe and well tolerated [15].

VTD slows down the absorption of some antibiotics (tetracycline, amoxicillin), thereby increasing their concentration in the gastric contents - the site of application in the treatment of helicobacteriosis. In vitro and in vivo studies have shown that VTD is synergistic with other antibiotics against H. pylori. Thanks to this property, it has become an indispensable component of anti-Helicobacter therapy, and its combination with two antibiotics is still called “classical triple therapy.” In addition, one of the ways to overcome H. pylori resistance is to use bismuth dicitrate as a base preparation of colloidal tripotassium. This position is confirmed by studying the in vitro antibacterial activity of combinations of various drugs with clarithromycin and amoxicillin against H. pylori strains sensitive or resistant to macrolides. It was shown that the properties of VTD played a decisive role in overcoming strain resistance and obtaining a persistent bactericidal effect of these drug combinations [16].

Numerous scientific studies conducted on the background of the use of bismuth tripotassium dicitrate for erosive and ulcerative lesions of various etiologies have shown that the drug has a wide range of cytoprotection mechanisms. VTD reduces pepsin activity (by 20–30%); selectively binds to the proteins of the bottom of the ulcer and creates a protective layer - a barrier to the diffusion of H+, which prevents damage to the area of ​​the mucous membrane (MU) of the stomach, devoid of a protective epithelial cover; stimulates local synthesis of prostaglandins (on average by 50%); increases the secretion of mucus and bicarbonates; increases local blood flow; suppresses the production of cytokines by cells of the inflammatory infiltrate; ensures reconstruction of the extracellular matrix and full angiogenesis; enhances the reparative effect mediated by epidermal growth factor. Morphologically, the mucous membrane of the gastroduodenal zone after healing of the ulcer is closer to the normal microstructure than when treated with other means. The use of high doses of VTD stimulates the production of prostaglandin E2 in gastric mucus, which is considered to be part of the mechanism that accelerates the healing of ulcerative lesions. Therapeutic doses of VDT cause sustained stimulation of prostaglandin production [17].

The mechanism of the antibacterial action of bismuth tripotassium dicitrate is associated not only with disruption of the adhesion of microorganisms to the epithelium of the mucous membrane, but also with disruption of ATP synthesis in the bacterial cell. Thus, in an in vitro study, incubation of H. pylori with tripotassium bismuth dicitrate led to a pronounced inhibition of the growth of the microorganism and its subsequent death [18]. Due to their anti-Helicobacter activity, colloidal bismuth preparations make it possible to increase or maintain the effectiveness of eradication therapy, especially in conditions of increasing antibiotic resistance of H. pylori. The anti-Helicobacter monoeffect of VTD averages 14–40%. The advantage of the drug is that there is no natural or acquired resistance of H. pylori to bismuth ions. Combination with antibiotics increases the degree of eradication to 50%, and the combination of two basic drugs - a proton pump inhibitor and bismuth tripotassium dicitrate - with two antibiotics makes it possible to overcome the resistance of H. pylori strains to nitrimidazole derivatives or clarithromycin.

Interesting results were presented by C. Srinarong et al. - 7-day standard triple therapy plus VTD and probiotic provided excellent eradication of H. pylori (100%) in areas with low clarithromycin resistance, such as Thailand, regardless of the CYP2C19 genotype of the pathogen [19].

In recent years, the importance of oxidative stress, potentiated by H. pylori bacteria (especially those with the CagA+/vacAs1 genotype), in the development of chronic gastritis has been shown [20]. Bismuth preparations turned out to be able to trap free oxygen radicals that are formed during oxidative stress and damage gastric mucosa, which serves as one of the components of their cytoprotective effect [21].

BTD has also proven itself well as a drug that can be successfully prescribed in the treatment of erosive and ulcerative lesions of the stomach and duodenum caused by taking non-steroidal anti-inflammatory drugs (NSAID-associated gastropathy). Thus, in a comparative study of the effectiveness of the use of VTD and ranitidine, healing of ulcers and multiple erosions of the stomach and duodenum after 4 weeks of treatment was achieved in 84.6% of patients receiving VTD, and only in 50% of patients receiving ranitidine [22]. In a comparative study on the effectiveness of using VTD (at a dose of 240 mg 2 times a day) in combination with a standard dose of omeprazole (20 mg per day) and omeprazole monotherapy in patients with NSAID-associated gastropathy, healing of erosive and ulcerative lesions of the stomach and duodenum after 2 weeks of treatment was achieved in 56.7% and 30.3% of patients, respectively, and after 4 weeks - in 100% and 93.9% of patients. An increase in the level of prostaglandins in the gastric mucosa, observed while taking VTD, indicated the cytoprotective effect of the drug [23, 24].

Due to their known antidiarrheal properties, bismuth compounds have been widely used to treat episodic diarrhea in children and adults for a century [25–28]. A number of studies have confirmed the effectiveness of bismuth subsalicylate in the prevention and treatment of traveler's diarrhea (E. coli enterotoxigenic). Enterotoxigenic E. coli was detected less frequently in travelers who received bismuth subsalicylate than in those who received placebo, demonstrating that bismuth subsalicylate prevents diarrhea by reducing the number and inhibiting the proliferation of enterotoxigenic E. coli [29].

Two studies reported the effectiveness of bismuth enema treatment for distal ulcerative colitis. Clinical and laboratory improvement was observed in 60% of patients resistant to conventional therapy, and 40% of patients achieved complete remission after 8 weeks of therapy [30]. A multicenter, double-blind, randomized, comparative study showed that when comparing the effectiveness of treatment with bismuth enemas with 5-aminosalicylic acid enemas, an equivalent therapeutic effect was established in the treatment of left-sided ulcerative colitis [31]. Oral bismuth is also effective for microscopic colitis [32] and as a colostomy deodorant [33].

In addition to its antibacterial properties [34, 25], bismuth also has anti-inflammatory effects [36] when passing through the intestines. There is experimental evidence supporting the role of bismuth in inhibiting the activity of inducible nitric oxide synthase in intestinal epithelial cells, as well as in the induction of heme oxygenase-1, thereby providing a therapeutic effect on inflammatory and oxidative reactions associated with inflammatory bowel diseases [37]. Another experimental study demonstrated the ability of bismuth to scavenge free radical oxygen in the context of chemical damage to the gastric mucosa [38]. Given these antibacterial and anti-inflammatory mechanisms, it can be theoretically assumed that bismuth should play a certain role in the pathogenetic treatment of acute and chronic diarrhea, as an antibacterial and antitoxic agent [39].

Hydrogen sulfide and other foul-smelling and toxic compounds are produced by colon bacteria when protein rots. In moderately severe ulcerative colitis [40], hydrogen sulfide is involved in inhibiting the oxidation of butyrate in the colon mucosa, which makes the mucosa more vulnerable to inflammatory agents [41, 42]. Bismuth, combining with hydrogen sulfide, forms insoluble, harmless bismuth sulfide and turns stool black [43].

The purpose of our original study was to evaluate the comparative characteristics of the infrared spectra (IR spectra) of two finished dosage forms of bismuth. The study analyzed the spectral characteristics of the most popular bismuth-containing drugs, namely the drugs De-Nol® (Netherlands) and Novobismol® (Russia). The active ingredient of these drugs is bismuth tripotassium dicitrate.

Spectral characteristics were obtained using an FSM-1202 infrared Fourier spectrometer (Russia). The pharmacologically active part of the tablet form was mixed with potassium bromide (Fluka, Germany) in a ratio of 1:100, and a disc was formed using a hydraulic press. The measurements were carried out in the range of 4000–400 cm-1, with a resolution of 4 cm-1 and a number of scans of 25. The device was controlled and data processed using the Fspec 4.0 program. The samples we studied had identical infrared spectra (Fig.).

The spectral characteristics of bismuth tripotassium dicitrate samples are interesting from the point of view of the spectral characteristics of the complex compound. Thus, in the spectrum of the samples, two characteristic broad absorption bands can be noted at 1579 and 1393 cm-1, caused by symmetric and asymmetric stretching vibrations in the COO fragment. This type of bond occurs in a chelate compound between the carboxyl groups of the citrate moieties and the complexing agent bismuth. It is this chelate form that causes a shift in the absorption bands corresponding to RCOO- and under normal conditions can be traced around 1560 and 1410 cm-1. It should be noted that similar shifts in the IR region of absorption bands for complex compounds of another type were previously described in the literature [44]. The absorption band at 1290 cm-1 found in the complex, in our opinion, is due to vibrations of C-O and O-Me (where Me are potassium or bismuth ions). It is the metal ions that cause the shift of the deformation (out-of-plane) vibrations of OH (950–900 cm-1) to a value of 845 cm-1, which corresponds to the bismuth complex under consideration. The vibrations of C-C bonds correspond to the absorption band at 910 cm-1. Accordingly, the bands at 1142, 1076, 1020 cm-1 are due to stretching vibrations of C-O and CH-O– fragments [45].

Thus, this study indicates almost complete pharmaceutical equivalence of the drugs we studied, De-Nol® and Novobismol®.

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E. Yu. Plotnikova1, Doctor of Medical Sciences, Professor A. S. Sukhikh, Candidate of Medical Sciences

State Budgetary Educational Institution of Higher Professional Education Kemerovo State Medical Academy of the Ministry of Health of the Russian Federation, Kemerovo

1 Contact information

* The drug is not registered in the Russian Federation.

pharmachologic effect

During therapy, it is possible to significantly reduce the production of pepsin and activate epidermal regeneration processes in areas of mucosal damage due to the bactericidal properties of bismuth dicitrate. The drug destroys Helicobacter pylori by destroying its cell membrane from the inside.

Thus, the compound accumulates in tissues and gradually leads to the elimination of the infection. Unlike antibiotics, bismuth-containing medications penetrate deep into the layers of duodenal mucus, where the pathogen is concentrated in maximum quantity.

The therapeutic effect of bismuth for gastritis and ulcers associated with Helicobacter pylori infection occurs without absorption - the substance is not absorbed by the walls of the digestive organs, and therefore does not affect the circulatory system. The component leaves the body in its original form.

At the same time, it would be incorrect to consider Bismuth tripotassium dicitrate as a completely safe drug. With prolonged use, the concentration of the active component in the cells of the central nervous system increases, which can lead to a number of side effects and complications.

The mechanism of pharmacological action of this drug is inextricably linked with the eradication of H. Pylori and the individual antibiotic resistance of the patient. It is also important to take into account the fact that on average no more than 30% of patients with peptic ulcers are carriers of the pathogenic microorganism.

Thus, bismuth preparations are not used as monotherapy. The maximum therapeutic effectiveness of the drug can be achieved by using it in combination with antibiotics and proton pump inhibitors.

The mechanism of action of bismuth tripotassium dicitrate is directly related to disturbances in the adhesive properties of the infectious agent and the synthesis of adenosine triphosphate in the pathogen cell itself. Conducted studies have repeatedly confirmed the effectiveness of incubation of H. Pylori and the pronounced inhibition of the vital processes of the bacterium in the future, up to its death.

Bismuth tripotassium dicitrate (patient reviews are not a basis for using the medicine without prior consultation with a doctor) can enhance the effectiveness of the course of eradication therapy, especially with the rapid development of pathogen resistance to a particular group of antibiotics.

The medication helps to quickly relieve dyspeptic disorders and other symptoms characteristic of ulcerative lesions.

Pharmacodynamics and pharmacokinetics

The substance has a pronounced astringent and anti-inflammatory effect. Once in the acidic environment of the stomach, bismuth oxychloride and bismuth citrate precipitate and form chelate complexes in the form of a protective film on the surface of the damaged mucosa. The product stimulates the synthesis of PgE2 , the secretion of bicarbonate and mucus, activates the protective properties of the gastric mucosa, thereby protecting the gastrointestinal tract from the effects of aggressive acids, salts and enzymes. In the area where the mucous membrane is damaged, epidermal growth factor . The activity of pepsin and pepsinogen begins to decrease.

Bismuth dicitrate accumulates inside Helicobacter and leads to the destruction of their cytoplasmic membrane and death. Due to the ability of the substance to penetrate under the layer of duodenal mucus , where the concentration of Helicobacter pylori is highest, its effectiveness in eradicating the Helicobacter is significantly higher than that of similar agents.

The medicine is not absorbed by the walls of the gastrointestinal tract and does not penetrate the systemic circulation. The unchanged substance is excreted in the feces. A small amount of the drug that penetrates the blood is metabolized and excreted in the urine.

Pharmacodynamics

When the pH level in the stomach changes, bismuth oxychloride and citrates, which are insoluble in water, fats, alkalis and acids, are converted into chelate-protein compounds. They create conditions for uniform coating of ulcerative surfaces with a polymer glycoprotein complex, a substance that protects the walls of the gastrointestinal tract better than the natural secreted mucous secretion.

The death of pathogenic bacteria occurs as a result of protein coagulation. Bismuth not only starts the healing process of peptic ulcers, but also reduces the likelihood of their recurrence. The drug increases the production of bicarbonate and mucin, as well as their quality indicators.

When taking Bismuth tripotassium dicitrate, ulcerative defects acquire a white foamy coating that lasts for 2-3 hours. In patients who were indicated for surgery, a few hours after taking the medicine, surgeons find a thin coating of bismuth film exclusively on the craters of ulcerations.

What are people saying?

Doctors have a positive opinion regarding Bismuth Tripotassium Dicitrate. In the reviews, they claim that the tablets have worked well for many reasons: they do not affect liver function, and also have several effects at once - bactericidal, astringent and anti-inflammatory. In addition, this medication perfectly relieves pain, even if it occurs in the patient due to a functional disorder.

Patients who have taken these pills also speak highly of them. The course should last at least a month, but for many the effect developed by the end of the second week. And although not everyone likes the taste of tablets, which leave a bitter taste in the mouth, the result is worth the patience.

Release forms. Trade names

All preparations based on bismuth tripotassium dicitrate are available in tablet form. Each tablet has a protective film shell, round or convex shape on both sides, white color and a mild specific odor.

Tablets with bismuth have a cross-section and are produced in cell contour blisters of 7, 10, 14 or 28 pieces. and in jars sealed with lids with a “push and turn” mechanism, 7, 14, 28, 56, 112 pcs.

In addition to the active component, which is bismuth tripotassium dicitrate, the tablets contain a whole complex of excipients.

All of them are used in the modern pharmaceutical industry:

• potassium polyacrylate;
• macrogol-6000;
• hypromellose;
• corn starch;
• magnesium stearate;
• titanium dioxide

  
  De-Nol is a complete analogue of Bismuth tripotassium dicitrate

Bismuth tripotassium dicitrate, according to reviews, is often found in pharmacies under other trade names.

The most popular and in demand drug is De-Nol.

There are also other gastroprotectors containing compounds with bismuth:

• Ulcavis;
• Vicanol;
• Novobismol;
• Ventrisol;
• Escape.

Indications for use

Medicines based on bismuth tripotassium dicitrate are included in the treatment of inflammatory pathologies of the digestive system. For chronic diseases accompanied by diarrhea and indigestion, such drugs are used as auxiliary drugs.

The annotation for tablets based on bismuth tripotassium dicitrate indicates the following indications:

• chronic gastritis in the acute stage;
• duodenitis;
• gastroduodenitis;
• irritable bowel syndrome;
• ulcerative lesions of the stomach and duodenum;
• infection with the bacterium Helicobacter pylori;

  

• other diseases of inorganic origin.

Taking Bismuth can improve your well-being, but it cannot be taken for unclear diagnoses in order to relieve symptoms. Also, gastroprotectors, to which this drug belongs, do not have indications for use for prophylactic purposes.

Bismuth tripotassium dicitrate
International name of the medicinal substance:
Bismuthate tripotassium dicitrate The list of drugs containing the active substance Bismuth tripotassium dicitrate is given after the description.
Pharmacological action:
Antiulcer agent with bactericidal activity against Helicobacter pylori, also has anti-inflammatory and astringent effects.
At pH 4 and below (gastric juice), insoluble bismuth oxychloride and citrate are precipitated, and chelate compounds are formed with the protein substrate (an insoluble protective coating at the site of the ulcer). By increasing the synthesis of PgE, which increases mucus formation and bicarbonate secretion, it stimulates the activity of cytoprotective mechanisms. Leads to the accumulation of epidermal growth factor in the defect area. Reduces the activity of pepsin and pepsinogen. Improves the protective properties of the gastrointestinal mucosa. Increases mucus production, resistance of the mucous membrane to the effects of pepsin, HCl and enzymes. Pharmacokinetics:
Practically not absorbed from the gastrointestinal tract. Excreted through the intestines, absorbed Bi - by the kidneys.

Indications:
Peptic ulcer of the stomach and duodenum (in the acute phase), chronic gastritis (including those associated with Helicobacter pylori);
dyspepsia not associated with organic gastrointestinal diseases. Contraindications:
Hypersensitivity, chronic renal failure, pregnancy, lactation.
Side effects:
Nausea, vomiting, diarrhea, allergic reactions.
With long-term use in high doses - encephalopathy associated with the accumulation of Bi in the central nervous system. Overdose. Symptoms: development of renal dysfunction. Treatment: gastric lavage, administration of activated charcoal and saline laxatives, symptomatic therapy; dialysis. Interaction:
30 minutes before and after the appointment, you should refrain from eating, antacid drugs and liquids.
Ethanol should not be consumed during therapy. Reduces the absorption of tetracycline. When used together with other Bi-containing drugs, the risk of side effects increases (increased Bi concentration in plasma). Locally acting antacids reduce the effect of bismuth tripotassium dicitrate. Special instructions:
During treatment, stool turns black.
Preparations containing the active ingredient Bismuth tripotassium dicitrate:
Bismopepsin, Bisnol, Ventrisol, Vikanol, Vikanol Life, Vitridinol, De-Nol, Novobismol, Pilocid, Tribimol, Trimo, Ulcavis, Heli-stop, Escape

The information provided in this section is intended for medical and pharmaceutical professionals and should not be used for self-medication. The information is provided for informational purposes only and cannot be considered official.

Contraindications

The drug has minimal restrictions on its use.

Among the main contraindications:

• children's age - up to 4 years, the drug is not used in treatment;
• allergic reaction;
• period of pregnancy and lactation.

Bismuth tripotassium dicitrate is prescribed to minor patients with extreme caution. Selecting the correct dosage requires special attention. Impaired kidney and liver function are also considered conditional restrictions on use.

Despite the fact that the drug is not involved in metabolic processes, its inclusion in the treatment program is carried out on the recommendation and under the supervision of a doctor. Information indicating the need to adjust the dose of bismuth for elderly patients has no official confirmation.

Side effect

The most common side effect, which is not a reason to discontinue the drug, is darkening of the stool. A change in the color of feces occurs against the background of the formation of the pigment compound bismuth sulfide in the intestines. This reaction is reversible. After stopping the intake of Bismuth Tripotassium Dicitrate, the stool acquires a natural color.

In addition, a common side reaction of the body to taking gastroprotectors are dyspeptic disorders such as:

• constipation;
• diarrhea;
• nausea;

  

• vomit;
• stomach ache.

With uncontrolled and prolonged use of the drug in high doses, there is a risk of developing encephalopathy. The disorder occurs due to the accumulation of bismuth in nerve cells.

Itching, burning, and rash on the skin indicate intolerance to the medicinal components included in the drug. If these symptoms do not go away after using an antihistamine, you should consult your doctor about discontinuing Bismuth tripotassium dicitrate and selecting an analogue.

In some cases, patients experience an increase in transaminase levels, which is short-term and disappears at the end of the course of treatment.

Side effects

If you take the medication, ignoring the instructions or medical advice, you will have to deal with unwanted reactions. Among them:

• Gastrointestinal tract: constipation, nausea, vomiting, increased desire for relief, as well as other transient effects.
• CNS: if you take this drug for a long time, encephalopathy may develop. All due to the accumulation of bismuth in the central nervous system.
• Skin: itching and skin rash.

But, as a rule, the tablets are tolerated by patients without problems. However, since the side effects are indicated in the instructions, then every person who is planning therapy should be aware of them.

special instructions

Bismuth tripotassium dicitrate (reviews are more often found about the drug with the trade name “De-Nol”) is recommended to be taken for no more than 8 weeks in a row. The dosage and duration of therapy should not be increased without a medical prescription. It is important to consider that at the end of treatment and over the next 2-3 months. You should not take any medications with bismuth.

Drinking alcoholic beverages during course therapy is not allowed. For patients whose professional activities involve driving complex machinery or vehicles, there are no restrictions during the period of taking tablets containing bismuth. There are no studies confirming the effect of this substance on psychomotor and cognitive functions.

Instructions for use Bismutha tetripotassium dicitrate

Bismuth tripotassium dicitrate (reviews prove that this drug is the undisputed leader among gastroprotectors) is used exclusively in oral form. The tablets must be swallowed with water.

Unlike a number of other medications, bismuth-based medications should not be taken with milk, tea or fruit juices. Chewing or crushing the tablets is also not allowed.

The dosage of the drug is selected individually by a specialist. The doctor takes into account the nature of the disease, the presence of concomitant pathologies in the patient and his tendency to allergic reactions.

The manufacturer recommends adherence to the following principles when establishing a treatment regimen for Bismuth tripotassium dicitrate:

The average duration of treatment is 1-2 months. When eradicating Helicobacter pylori, the drug is recommended to be used in combination with antibacterial drugs prescribed by a doctor.

Bismuth tripotassium dicitrate in the treatment of patients with post-infectious irritable bowel syndrome

Parfenov A.I., Ruchkina I.N., Osipov G.A.

It is known that in the anamnesis of many patients with irritable bowel syndrome (IBS) there are references to acute intestinal infections (AII), and in some patients after AII, despite the absence of bacteriological and immunological signs of intestinal infection, intestinal symptoms persist for a long time [2,3 ]. So, V.M. Bondarenko et al. When stool cultures were taken from patients after acute intestinal infections, pronounced changes in the microflora were found [1,4]. At the same time, there were no bacteriological and immunological signs of intestinal infection. I.N. Ruchkina, based on the experience of 750 patients, identified an etiotropic and pathogenetic connection between IBS and intestinal infection in 71% of cases, which made it possible to call this condition post-infectious irritable bowel syndrome (PSIBS) [7,8].

Below are the clinical and laboratory criteria characteristic of PSCC.

• Mention in the anamnesis of acute intestinal infections that preceded the disease.
• Detection of markers of acute intestinal infections in the biological media of the patient.
• Signs of dysbiosis in bacteriological cultures of feces.
• Bacterial overgrowth in the small intestine
• Reduced immune tension.
• Positive effect of therapy with biologically active drugs, pre- and probiotics.

The purpose of this work is to study the effectiveness of bismuth tripotassium dicitrate (De-Nol) in the treatment of PSCC with predominant diarrhea and its effect on the composition of the intestinal microflora.

The decision to use De-Nol for the treatment of patients with PSCC was based on the results of studies that proved that the drug is successfully used in eradication therapy of Helicobacter pylori, inhibiting the growth of the microorganism on the gastric mucosa [5]. The therapeutic effect is based on the bactericidal properties of the drug, which forms complexes on the bacterial wall, inhibits bacterial enzymes (urease, catalase and lipase, etc.), preventing the adhesion of H. pylori to gastric epithelial cells. In addition, bismuth preparations are traditionally used as astringents for inflammatory diseases of the gastrointestinal tract.

Material and methods

20 patients with PSCC with predominant diarrhea were under observation. The comparison group consisted of 10 patients with IBS with a predominance of diarrhea, matched by gender and age.

Patients associated the onset of the disease with food poisoning, for which they were examined and treated on an outpatient basis at the place of residence or in an infectious diseases hospital. Due to ongoing complaints, patients were usually prescribed stool tests, which determined dysbacteriosis in the absence of growth of pathogenic microflora. Patients were prescribed adsorbents, probiotics, loperamide, and enzyme preparations. However, drug therapy did not have a lasting positive effect, which was the basis for referral to TsNIIG.

Upon admission, patients complained of loose stools up to 4-6 times a day (mainly in the morning, not abundant, mixed with mucus), flatulence, bloating, pain and discomfort in the abdomen (usually in the left side). The pain was cramping in nature and subsided or decreased after defecation. There were no symptoms of “anxiety”, thus the diagnosis of IBS met the Rome II criteria.

At the clinic, patients underwent standard laboratory and instrumental examination, incl. colonoscopy. To solve the problems, patients in the study group underwent esophagogastrointestinoscopy with multiple biopsies of the small intestinal mucosa. In addition to histological examination, the composition of mucosal microflora was determined in biopsy specimens.

The mucous flora was studied using gas chromatography combined with mass spectrometry (GC-MS). A specialized chromatograph, Microbial Identification System, manufactured by MIDI Inc., Delaware, USA, was used. The principle of the method is molecular, based on the direct determination of fatty acids (FAs) of the cell wall of microorganisms in a biosample and allows the identification of up to several thousand strains of bacteria and microscopic fungi [6]. Features of fatty acid composition are used along with other parameters in bacterial taxonomy and clinical bacterial diagnostics. The study was carried out twice - before and after therapy.

The composition of fecal microflora was studied by bacteriological method. The study of mucosal and fecal microflora was carried out at the beginning and at the end of the hospital stay.

Patients were prescribed diet 4b, drotaverine hydrochloride for abdominal pain (2 tablets as required, up to 3 times a day) and multivitamins. Patients in the study group were prescribed De-Nol 120 mg 3 times a day, and patients in the comparison group were prescribed an antacid 3 sachets per day. Both drugs were prescribed 30 minutes before. before meals, 3 times a day, for 3 weeks.

The effectiveness of the therapy was assessed by the dynamics of clinical symptoms, changes in the composition of fecal and mucosal microflora of the small intestine.

Results and discussion

Positive dynamics in patients in the study group began to appear after a week:

• The frequency of stools decreased to 2-3 times/day, the stool became more formed, the admixture of mucus in it decreased;
• flatulence and rumbling in the stomach decreased;
• Abdominal pain was less common.

By the beginning of the third week, 16 patients experienced stable clinical remission of the disease, and 4 had a decrease in its manifestations.

In the comparison group, none of the patients experienced improvement, and therefore, starting from the second week, they were prescribed standard complex therapy for IBS. It included: antispasmodics, intestinal antiseptics followed by a long course of one of the probiotics, and for flatulence - activated charcoal.

Before treatment, all patients had a decrease in the number of normal flora of the colon, bifidobacteria, lactobacilli, and bacteroides, and an increase in opportunistic microorganisms. No pathogenic microorganisms were detected.

After treatment with De-Nol, the microbial profile of feces improved. Firstly, the amount of opportunistic microflora decreased: hemolyzing Escherichia coli, cocci, clostridia, Klebsiella, Proteus and Candida were detected less frequently. Secondly, the number of lacto- and bifidobacteria has increased (on average by an order of magnitude).

The most interesting changes, in our opinion, occurred in the composition of mucosal microflora, studied using the GC-MS method. With its help, it was possible to measure the abundance of 57 taxa of intestinal microorganisms.

Analysis of the microbial composition of the mucosal microflora of the jejunum in patients with IBS with diarrhea showed various deviations compared with indicators of healthy people. In all patients, the total content of normal flora was reduced by 7-8 times compared to the norm, with a simultaneous increase in opportunistic microflora. After a 3-week course of treatment with De-Nol, the number of a number of microorganisms began to approach normal, mainly due to a decrease in the concentration of opportunistic microorganisms.

A decrease in the number of actinobacteria (Actinomyces, Streptomyces, Nocardia), fungi and cytomegalovirus was also revealed. The number of cocci (staphylococci, enterococci, enterococci), which initially exceeded the norm, noticeably decreased compared to the norm. Number of Cl. difficile and Cl. perfringes did not exceed the norm, however, their number after treatment decreased by 20-60%.

Unlike antibiotics, De-Nol does not suppress normal intestinal microflora. Thus, using the example of bifidobacteria, we can demonstrate the stabilizing effect of De-Nol on the microbial community. As a result of treatment, there was a decrease or increase to normal in the number of bifidobacteria and a noticeable absence of the inhibitory effect of the drug, although their content was initially normal.

The concentration of other main normal inhabitants of the jejunal mucosa - eubacteria (E. moniliforme, E. nodatum, E. sabureum, etc.), as well as propionic bacteria - also leveled out.

Concentration of Propionibacterium spp. - normal inhabitants of the mucosal microflora of the jejunum, with an initial low level (one to two orders of magnitude below the norm) after a course of De-Nol, increased in number and approached the norm.

There was a tendency towards quantitative normalization of the microbiota of the jejunal mucosa: a decrease in the concentration of microbes exhibiting excessive growth and an increase in the number of deficient microbes. However, complete recovery was not observed, which was the reason for continuing treatment of these patients with pro- and prebiotics.

Thus, in all patients with IBS, after completing the De-Nol course, positive dynamics were obtained in the composition of the fecal and mucosal microflora of the jejunum, manifested primarily by a decrease in the concentration of opportunistic microflora.

In the comparison group, patients with IBS did not achieve a significant improvement in the composition of the intestinal microflora while taking antacids and diet therapy. In repeated stool cultures, the deficiency of bifidobacteria and lactobacilli remained, and the indicators of opportunistic microflora remained elevated.

Thus, the cause of the development of IBS in our patients was a pronounced change in the eubiosis of the jejunal mucosa and the composition of the fecal microflora. In all patients, stool cultures revealed a decrease in the concentration of bifidumbacteria and lactobacilli. At the same time, there was an increase in opportunistic microflora, most often yeast-like fungi, microflora cocci, clostridia, Proteus, and Klebsiella. It should be noted that the growth of pathogenic enterobacteria was not observed in any patient. All patients with IBS with diarrhea had significant disturbances in the mucosal microflora of the jejunum, which was manifested by changes in up to 57 microbial taxa identified using GC-MS. There was a significant decrease in the concentration of normal flora (up to 15-20 times) with a simultaneous increase in opportunistic microflora.

As a result of a 3-week course of De-Nol, a positive dynamics of the course of IBS with a predominance of diarrhea was obtained, characterized by a decrease in the frequency of stools, pain and flatulence. The effectiveness of De-Nol in the treatment of patients with IBS with a predominance of diarrhea is explained by a number of reasons.

In the group of patients with IBS associated with intestinal dysbiosis, after a 3-week course of De-Nol, remission of IBS was achieved and the composition of mucosal and fecal microflora improved. At the same time, there was a decrease in the concentration of opportunistic microflora and a secondary growth of normal microflora. The number of cocci, actinobacteria (Actinomyces, Streptomyces, Nocardia), clostridia, fungi and cytomegalovirus decreased noticeably. A tendency towards an increase in normal flora with a simultaneous improvement in the ratio of various groups of microorganisms in the microbial community of the jejunal mucosa was revealed.

It must be emphasized that, unlike antibiotics, De-Nol does not suppress the growth of normal flora in various parts of the intestine. The drug has a wide antibacterial spectrum of activity and can be prescribed as an intestinal antiseptic. In addition, bismuth, which is part of the drug, has an astringent effect, which leads to a slowdown in intestinal motility and contributes to the onset of remission of IBS with a predominance of diarrhea.

In the comparison group, no significant improvement was achieved. Along with clinical symptoms, disturbances in intestinal microflora persisted. In this connection, as already mentioned, these patients were prescribed standard therapy for IBS.

Thus, as a result of a 3-week course of therapy with De-Nol, a significant positive dynamics of the course of PSCC with a predominance of diarrhea was obtained, characterized by the onset of remission and restoration of intestinal eubiosis.

conclusions

• All patients with post-infectious IBS associated with intestinal dysbiosis, after a 3-week course of De-Nol, achieved clinical remission and improvement in the composition of the intestinal microflora.
• De-Nol can be included in the complex therapy of patients with IBS associated with intestinal dysbiosis.
• De-Nol can be considered as an intestinal antiseptic, the mechanism of action of which is associated with the ability to suppress the growth of opportunistic microflora.

Literature 1. Bondarenko V.M., Gracheva N.M., Matsulevich T.V. Intestinal dysbiosis in adults. KMK Scientific Press, Moscow 2003, 220p] 2. Brodov L.E. Foodborne toxic infections as a risk factor for the development of some acute and exacerbation of chronic diseases. Ter. Arch..1993;5: 77-80; 3. Vorobyov G.I., Simkina E.S. Principles of organizing the prevention of colon diseases, taking into account epidemiological experience. Ter. arch.1994;2:53-55] 4. Grigoriev P.Ya., Yakovenko E.P. Irritable bowel syndrome associated with dysbiosis // Consilium medicum - 2003.- T. 2, No. 7.- P. 305-307. 5. Lapina T.L. Russian recommendations for the diagnosis and treatment of Helicobacter pylori infection. In the book: Ivashkin V.T. et al. Helicobacter pylori: revolution in gastroenterology. - M., "Triad-X", 1999, 161 - 174 6. Osipov G.A. , Parfenov A.I., Verkhovtseva N.V. , Ruchkina I.N. and others. Clinical significance of the study of microorganisms of the intestinal mucosa using cultural-biochemical and chromatography-mass spectrometric methods. // Experiment. and clinical gastroenterology. 2003. - No. 4.-P.59-62. 7. Parfenov A.I., Ruchkina I.N., Potapova V.B., Osipov G.A. Post-infectious irritable bowel syndrome or chronic colitis? Materials of the V Congress of the Society of Gastroentertics. Russia and the XXXII session of the TsNIIG, Moscow February 3-6, 2005 - M.: Anacharsis, 2005. - P 482-483] 8. Ruchkina I.N. The role of acute intestinal infections and microbiocenosis disorders in the etiology and pathogenesis of irritable bowel syndrome. Author's abstract. Diss. doc. M.: 2005: 40 p.].

Overdose

By adhering to the instructions, patients eliminate the possibility of an overdose. Normally, the concentration of bismuth in blood plasma should not exceed 58 mcg/l. When this substance accumulates in an amount of 100 μg/l, which is achieved with long-term use of bismuth in an excessive dosage, clinical manifestations of an overdose of this medicinal substance are possible.

Thus, in case of Bismuth poisoning with tripotassium dicitrate, the following are observed:

• severe dyspepsia;
• hyperemia and swelling of the oral mucosa;
• skin rashes of any location;
• darkening of the gums and tongue.

There are no special drugs that neutralize the effects of bismuth poisoning.

In case of overdose, the same measures must be taken as in case of food or drug poisoning:

• rinse the stomach with plenty of water;
• take enterosorbents;
• use drugs that restore water and electrolyte balance in the body.

  

Severe intoxication may be a reason to prescribe dimercaptosuccinic or dimercaptopropanesulfonic acids, as well as hemodialysis (hardware blood purification).

Interaction with other drugs

The drug can be used simultaneously with other medications.

In this case, you should adhere to the following nuances:

• Half an hour before and after taking Bismuth tripotassium dicitrate tablets, it is undesirable to consume any food or drinks.
• Antacid drugs can inhibit the gastroprotective properties of the main component.
• When eradicating Helicobacter pylori, tetracyclines are not used, since bismuth blocks their absorption.

To avoid overdose and the development of complications from the central nervous system, it is undesirable to take analogues in parallel with Bismuth tripotassium dicitrate.

Indications

The instructions for use of “Bismuth tripotassium dicitrate” list the conditions for which this remedy can be prescribed. Indications include the following diseases:

• Gastroduodenitis and chronic gastritis, which are in the acute phase. Including the one associated with Helicobacter pylori.
• Functional dyspepsia resulting from non-organic gastrointestinal diseases.
• Ulcer of the duodenum and stomach, which is in the acute phase.
• Irritable bowel syndrome, which causes symptoms of diarrhea.

And even though this product is sold in a pharmacy without a prescription, there is no need to self-medicate. Is it dangerous! Any drug has its contraindications and side effects, including tablets with bismuth tripotassium dicitrate. And you will learn about them further.

Analogs

Gastroprotectors used for the same indications as Bismuth tripotassium dicitrate can be divided into 2 categories. The first includes drugs that form a film covering of ulcers and erosions. These are drugs that have an identical or similar composition, but different trade names.

Thus, popular analogues of Bismuth tripotassium dicitrate are:

• De-Nol;
• Novobismol;

  

• Ulcavis.

Also classified as film-forming drugs are the gastroprotective drugs Sucralfat, Venter, Sukrat. Their active ingredient is aluminum salt. If patients are intolerant to tripotassium bismuth, patients are sometimes prescribed basic bismuth nitrate, which is present in the combination medications Vikalin and Vikair.

Non-film-forming drugs are aimed at eliminating the physiological causes of diseases. Their mechanism of action is based on synthesis with mucosal proteins and the production of protective mucus in the stomach.

For Helicobacter pylori infection, such analogs of Bismuth tripotassium dicitrate, as a rule, are not used:

• Biogastron;
• Duogastron;
• Topogin;
• Peaceful.

Price

The average cost of a package with 56 tablets is currently about 240 rubles. De-Nol is more often available and is considered a more popular gastroprotector, which contains bismuth tripotassium dicitrate. Its cost is 2-2.5 times higher than the drug of the same name.

Medicines containing bismuth tripotassium dicitrate, judging by reviews, are an integral part of the treatment of inflammatory pathologies of the gastrointestinal tract. Bismuth compounds have been used in medical practice since 1786 - it was then that the first scientific report on a medicine with bismuth was presented.