What Are the Most Common Uses for Bismuth Subsalicylate?

Bismuth is a kind of mucosal protective agent. It produces a precipitate in an acidic environment and forms a diffuse protective layer covering the ulcer surface, which promotes the regeneration of ulcer mucosa and the healing of ulcers. At the same time, it has the effects of reducing pepsin activity, increasing mucin secretion, and promoting the release of prostaglandin 2 (PGE2) from the mucosa, thereby protecting the mucosa. Inhibition of Helicobacter pylori (Hp) mainly works by inhibiting the proteases, urokinase and phospholipase produced by Hp.

Bismuth I. Overview

Bismuth is widely used in the treatment of peptic ulcer, eradication of H. pylori (Hp), prevention and treatment of diarrhea. However, the pros and cons of bismuth in clinical applications are constantly controversial, and its understanding and application are constantly changing. After being absorbed by the body, bismuth is mainly distributed in the kidney, brain, liver, spleen and bones. It has a certain toxic effect on these organs, and there is an unreasonable drug use phenomenon in primary medical institutions, so there is a potential risk of drug use. Bismuth is mainly metabolized by the kidneys and binds to bismuth metal-binding protein in the kidney, so bismuth has some renal toxicity. In addition, long-term application of bismuth can cause neuropathy, encephalopathy, osteoarthropathy, gingivitis, stomatitis and colitis.

Bismuth Agent 2. Development History

Bismuth has been used clinically for more than 200 years. Currently, the most commonly used bismuth is bismuth potassium osmate, colloidal pectin bismuth, and bismuth hyposalicylate. In the 1970s, bismuth was mainly used in Australia and France. In Australia, bismuth gallate is used to deodorize stools of patients with colostomy. In France, bismuth salts are widely used in the treatment of many gastrointestinal diseases. In the 1970s, France, Australia, Brazil and other countries began to report bismuth encephalopathy caused by taking bismuth, especially in 1972-1977, France had a large dose and long-term use of bismuth caused fatal encephalopathy. Since then, the use of bismuth has caused panic and attention, and gradually faded out of the clinic. Since Marshall reported in 1985 that bismuth can kill Hp, a large number of applications of bismuth have made a comeback. In the eradication of Hp, bismuth as a member of the quadruple therapy has reached consensus in the industry. At the same time, there are many cases of related adverse reactions caused by it.

In the context of high Hp resistance rates, the bismuth quadruple regimen has again attracted attention: the efficacy of the classic bismuth quadruple regimen (bismuth + PPI + tetracycline + metronidazole) has been confirmed again. In the latest Maastricht-IV consensus, the first-line solution is in areas with high resistance to clarithromycin (> 15%). First, a quadruple solution of bismuth is recommended. If no bismuth, sequential or concomitant therapy is recommended. In addition to the standard triple therapy, low-drug resistance rates are also recommended as a first-line treatment. In short, in the face of the challenge of rising antimicrobial resistance rates, bismuth quadruple therapy has once again received attention. Bismuth agents are still widely available in China, and we must make full use of this advantage.

Bismuth III. Mechanism

There is no authoritative explanation of the effect of bismuth on gastric abdomen, and the general view is that it may have the following effects.

1. Physiological protection: Water-soluble colloidal bismuth becomes insoluble precipitate under the action of gastric acid, and combines with proteins on the surface of ulcers or inflammation sites to form a protective film to strengthen the gastric barrier membrane.

2. Cytoprotective effect: By increasing prostaglandin synthesis in the parietal membrane cells, thereby improving the quality of the parietal fluid, stimulating the secretion of bicarbonate, improving the gastric mucosal blood flow, and promoting epithelial regeneration.

3. Bismuth can enter the human body and gather in Hp bacteria, causing it to contract irregularly, rupture the bacterial membrane, and eventually kill HPo, which causes inflammation of the gastric membrane, ulcers and recurrence.

4. It may also inactivate with pepsin.

Bismuth

At present, bismuth is mainly used in the treatment of Hp eradication, but how to apply it is still controversial. Due to cultural differences and social and economic conditions, the infection rate of Hp in China recently was 40% to 85%, with an average of 59%. A multi-center study in China shows that the average resistance rates to metronidazole and clarithromycin have reached 75.6% and 27.6%, and the eradication rate of classic triple therapy has been lower than 80%, so exploring new first-line eradication programs has been Becoming a top priority for clinical work. Some studies suggest that large doses and long-term use of bismuth can cause serious adverse reactions such as neurotoxicity. Many developed countries in the west have banned the clinical application of bismuth. A number of foreign studies recently recommended the classic quadruple regimen, quinolone-containing regimen, sequential regimen, and bismuth-free quadruple regimen to replace the classic triple regimen to improve the eradication efficacy of Hp, but its application effect and safety in China have not been Reach consensus.

In China, the quadruple therapy containing bismuth was recommended as the second-line solution in the Lushan Consensus in 2007. The fourth national consensus report on the management of Helicobacter pylori infection in 2012 stated that the eradication protocol recommended a quadruple therapy consisting of bismuth + PPl + 2 antibacterial drugs.

October 8-9, 2015, Management of Helicobacter pylori infection: The Maastricht V consensus meeting was held in Florence, Italy, and the "Kyoto Global Consensus of Helicobacter Pylori Gastritis" ("Kyoto Consensus" for short) was published. In areas with high clarithromycin resistance (> 15%), bismuth quadruple therapy or non-bismuth quadruple concomitant therapy (PPI + amoxicillin + clarithromycin + metronidazole) is recommended. In areas with high dual resistance rates of clarithromycin and metronidazole, a bismuth quadruple regimen is recommended as first-line therapy. Level of evidence: Low; Level of recommendation: Strong. The bismuth quadruple regimen became the main eradication regime. Also recommended in this consensus. In fact, in areas where the dual resistance rate of clarithromycin and metronidazole is> 15%, the consensus no longer recommends the non-bismuth quadruple regimen, and the recommended first-line, second-line, and third-line empirical treatment are all bismuth quadruple regimens This is very similar to the plan recommended by our consensus in 2012. Bismuth has the effect of directly killing Hp, does not produce drug resistance, can increase the eradication rate of resistant strains, and has good short-term application safety. These are the reasons for the consensus to strongly recommend the bismuth quadruple scheme.

Bismuth V. Adverse reactions

The application of bismuth does solve some problems in clinical practice. However, since the 1970s, adverse reactions caused by it have been reported in individual cases. Taking a regular dose of bismuth, the content of bismuth in the body is low, and the possibility of toxic effects is small, but there may also be adverse reactions such as liver and kidney damage, skin rubella, and dermatitis. Large doses of bismuth can cause irreversible vertebral extracorporeal injury and renal failure. More importantly, the damage of heavy metal bismuth to the brain and kidney has not yet attracted the attention of relevant specialists, and the corresponding examinations are also blank. Therefore, for patients with long-term and repeated use of bismuth, attention should be paid to the potential risks of bismuth accumulation in the body. .

1. Nervous system: Bismuth encephalopathy was first discovered in Australia in 1973, and later reported in France and Western Europe. In 1979, 945 cases of bismuth encephalopathy were reported in France, of which 72 died. In Australia, more than 1,000 cases of bismuth encephalopathy have been reported. Data evaluations in France and Australia show that the risk of bismuth poisoning must be noted when using large doses (metal bismuth ingestion> 1.5g / d) and long-term use (months to years). The blood bismuth level of bismuth poisoning encephalopathy is 100ug / L, reaching 50 to 100}, and g / L should be highly vigilant. A case of bismuth encephalopathy caused by a patient with chronic renal failure after taking a conventional therapeutic dose of bismuth was reported in 1990 ^[1] .

2. Digestive system: During taking bismuth, there may be ammonia smell in the mouth, and sometimes black fluffy tongue coating appears. Other gastrointestinal side effects are diarrhea, bismuth in stool, and grayish black stool, which is easily confused with black stool in upper gastrointestinal bleeding. Can disappear after stopping the medicine.

3. Urinary system: Bismuth is mainly absorbed in the duodenum, jejunum, and ileum. After entering the blood circulation, it is excreted by the kidneys. After using the regular dosage (480mg / d) of bismuth for 4 weeks, the blood concentration is 7.0ug / L, and the daily renal excretion rate is 2.6%. The bismuth concentration in the urine can be restored to the pre-dose level after the drug is stopped for 60 days. Renal failure. In 1992, Lancet reported that acute renal failure caused by excessive use of bismuth agent once again caused people's attention to bismuth agent.

4. Skeletal muscle system: Adverse reactions of the bone often occur in different parts, which are related to the high concentration of bismuth in the bone. More common are osteoarthritis associated with bismuth encephalopathy, which is usually preceded by unilateral or bilateral shoulder pain, which accounts for about 3.0% of encephalopathy.

5. Drug interactions: Colloidal bismuth osmic acid is a complex salt of bismuth hydroxide and osmic acid. This macromolecule is in a colloidal state in aqueous or alkaline solution, and it is in an acidic environment (pH <5 ) Loss of stability. Spenard et al. Conducted a randomized controlled trial involving 36 healthy subjects to investigate the bioavailability of omepramine in bismuth in "three-in-one" capsules (140 mg bismuth citrate + 125 mg metronidazole + 125 mg tetracycline hydrochloride) The effects of PPI preparations have also been experimentally demonstrated to increase the absorption of bismuth. Therefore, it is necessary to be vigilant in clinical practice of the possible harm of PPI preparations to promote the absorption of bismuth. It is not difficult to find that it is mentioned in various clinical drug manuals: acid inhibitors can increase the absorption of bismuth into the blood, and it should not be taken at the same time as bismuth.

Bismuth

1 Allergic to this drug, severe renal insufficiency, pregnant women should be contraindicated.

2. It is normal for the stool to be dark brown during medication.

3. For lactating women, breastfeeding should be suspended.

4. People who are allergic to aspirin, salicylate and temperature rise should not take bismuth. Patients with hyponatremia, hypoglycemia, diarrhea and liver and kidney dysfunction for more than 24 hours should be used with caution. Bismuth should not be taken more than 4 times within 24 hours, and continuous medication should not be longer than 8 weeks. In the eradication of Hp, it should not be longer than 3 weeks.

5 Due to the interaction between bismuth and tetracycline, probenecid, methotrexate, warfarin and other drugs, it should not be combined.

6 Do not take with milk.