Bismuth subsalicylate

Bismuth subsalicylate is an Anti-secretory drug belonging to an Antidiarrheal / Anti-inflammatory agent.

Bismuth subsalicylate is an antidiarrheal and anti-inflammatory agent used for the symptomatic treatment of nausea, indigestion, upset stomach, diarrhea, and other temporary discomforts of the stomach and gastrointestinal tract.

Less than 1% of bismuth from oral doses of bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation. Absorbed bismuth is distributed throughout the body. Bismuth is highly bound to plasma proteins (> 90%). Bismuth has multiple disposition half-lives with an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days. Elimination of bismuth is primarily through urinary and biliary routes with a renal clearance of 50 ± 18 mL/min.

Bismuth subsalicylate shows side effects like Anxiety, loss of hearing, confusion, constipation, diarrhea, difficulty in speaking or slurred speech, dizziness or lightheadedness, Drowsiness, fast or deep breathing, headache, increased sweating, increased thirst, mental depression, muscle spasms (especially of the face, neck, and back), muscle weakness, nausea or vomiting, ringing or buzzing in ears, stomach pain, trembling, uncontrollable flapping movements of the hands (especially in elderly patients) or other uncontrolled body movements, vision problems.

Bismuth subsalicylate is available in the form of Oral tablets and Oral suspension.

Bismuth subsalicylate is available in India, the US, Canada, Spain, China, Japan, France, Italy, and Australia.

Bismuth subsalicylate belongs to the Antidiarrheal / Anti-inflammatory agent and acts as an Anti-secretory drug.

Bismuth subsalicylate exhibits both antisecretory and antimicrobial action. This agent may provide some anti-inflammatory action as well. The salicylate moiety provides an antisecretory effect and the bismuth exhibits antimicrobial directly against bacterial and viral gastrointestinal pathogens.

The Onset and duration of Bismuth subsalicylate are not clinically established.

Bismuth subsalicylate is an antidiarrheal and anti-inflammatory agent used for symptomatic treatment of nausea, indigestion, upset stomach, diarrhea, and other temporary discomforts of the stomach and gastrointestinal tract.

Bismuth subsalicylate is approved for use in the following clinical indications

Adult indication

• Diarrhea/dyspepsia
• Helicobacter pylori eradication
• Travelers' diarrhea, prophylaxis
• Travelers' diarrhea, treatment

Pediatric indication

• Diarrhea, chronic
• Diarrhea, dyspepsia, acute
• Helicobacter pylori eradication
• Travelers diarrhea

Adult Dose

• Diarrhea/dyspepsia

Oral: ~524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days.

• Helicobacter pylori eradication

Oral: 300 mg 4 times daily in combination with tetracycline 500 mg 4 times daily, either metronidazole 500 mg 3 or 4 times daily or 250 mg 4 times daily, and standard-dose proton pump inhibitor twice daily; continue regimen for 10 to 14 days.

• Travelers' diarrhea, prophylaxis

Oral: ~524 mg 4 times daily with meals and at bedtime during periods of risk.

• Travelers' diarrhea, treatment

Oral: ~524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed.

Pediatric Dose

• Diarrhea, chronic

Infants ≥2 months: Oral: 44 mg every 4 to 6 hours.

Children <2 years: Oral: 44 mg every 4 hours or 87 mg every 6 hours.

Children 2 to <3 years: Oral: 87 mg every 4 to 6 hours.

Children 3 to <4 years: Oral: 87 mg every 4 hours.

Children 4 to 6 years: Oral: 175 mg every 4 hours.

• Diarrhea, dyspepsia, acute

Children ≥12 years and Adolescents: Oral: 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days. Maximum daily dose: 4,200 mg/day.

• Helicobacter pylori eradication

Children and Adolescents

<10 years: Oral: 262 mg 4 times daily.

≥10 years: Oral: 524 mg 4 times daily.

• Travelers diarrhea

Children 3 to <6 years: Oral: 87 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.

Children 6 to <9 years: Oral: 175 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.

Children 9 to <12 years: Oral: 262 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.

Children ≥12 years and Adolescents: Oral: 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed; maximum dose: 4,200 mg per 24 hours.

Bismuth subsalicylate is available in various strengths as 262 mg/15 mL; 262 mg; 525 mg/15 mL; 527 mg/30 mL; 690 mg/30 mL; 525 mg/30 mL; 1050 mg/10 mL; 300 mg; 524 mg/15 mL; 524 mg/30 mL.

Bismuth subsalicylate is available in the form of Oral Tablets and Oral suspension.

Bismuth subsalicylate is contraindicated in patients with

• Methoxyflurane

Do not administer methoxyflurane to patients taking Bismuth Subsalicylate Therapy. The concurrent use of tetracycline hydrochloride, a component of Bismuth Subsalicylate Therapy with methoxyflurane has been reported to result in fatal renal toxicity.

• Disulfiram

Bismuth Subsalicylate Therapy is contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions have been reported in alcoholic patients who are using metronidazole, a component of Bismuth Subsalicylate Therapy, and disulfiram concurrently.

• Gastrointestinal toxicity: Constipation has been reported in clinical trials. Although rarely serious, some events resulted in hospitalization, intestinal perforation, or bowel obstruction (these events occurred at a dose higher than the recommended dose). Patients with advanced carcinoid tumors may be at risk for altered gastrointestinal tract wall integrity; monitor closely for constipation and/or severe, persistent, or worsening abdominal pain. Discontinue for severe constipation and/or the development of severe persistent or worsening abdominal pain.

Alcoholic beverages or other products containing propylene glycol should not be consumed during and for at least 3 days after usage of Bismuth Subsalicylate Therapy. A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol, a component of Bismuth Subsalicylate Therapy.

Bismuth subsalicylate is not recommended for use in breastfeeding women unless necessary. The risks and benefits should be considered before taking Bismuth subsalicylate.

Common

● Esophagitis (acute esophageal necrosis), melena, melanoglossia, staining of the tooth, Anaphylaxis, Encephalopathy, Tinnitus.

• Methoxyflurane

Do not administer methoxyflurane to patients taking Bismuth Subsalicylate Therapy. The concurrent use of tetracycline hydrochloride, a component of Bismuth Subsalicylate Therapy, with methoxyflurane has been reported to result in fatal renal toxicity.

• Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Bismuth Subsalicylate Therapy should not be given to patients who have taken disulfiram within the last 2 weeks.

• Alcohol

Consumption of alcoholic beverages or administration of other products containing propylene glycol during treatment with Bismuth Subsalicylate Therapy and for at least 3 days afterwards may cause a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) due to the interaction between alcohol or propylene glycol and metronidazole, a component of Bismuth Subsalicylate Therapy. Discontinue alcoholic beverage or other products containing propylene glycol during and for at least 3 days after therapy with Bismuth Subsalicylate Therapy.

• Oral Contraceptives

Concurrent use of Bismuth Subsalicylate Therapy with oral contraceptive may make oral contraceptives less effective due to an interaction with the tetracycline component of Bismuth Subsalicylate Therapy. Breakthrough bleeding has been reported. Women of childbearing potential should use a different or additional form of contraception while taking Bismuth Subsalicylate Therapy.

• Anticoagulants

Bismuth Subsalicylate Therapy may alter the anticoagulant effects of warfarin and other oral coumarin anticoagulants. Salicylates may cause an increased risk of bleeding when administered with anticoagulant therapy. Metronidazole has been reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. Tetracycline has been shown to depress plasma prothrombin activity. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if Bismuth Subsalicylate Therapy is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.

• Lithium

In patients stabilized on relatively high doses of lithium, short-term use of Bismuth Subsalicylate Therapy may cause elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Serum lithium and serum creatinine concentrations should be monitored several days after beginning treatment with Bismuth Subsalicylate Therapy to detect any increase that may precede clinical symptoms of lithium toxicity.

• Antacids, Multivitamins, Or Dairy Products

The absorption of Bismuth Subsalicylate Therapy may be reduced if administered with antacids containing aluminium, calcium, or magnesium; preparations containing iron, zinc, or sodium bicarbonate; or milk or dairy products due to the interaction between these products and tetracycline. These products should not be consumed concomitantly with Bismuth Subsalicylate Therapy. However, the clinical significance of reduced tetracycline systemic exposure is unknown as the relative contribution of systemic versus local antimicrobial activity against Helicobacter pylori has not been established.

• Antidiabetic Agents, Aspirin, Probenecid, Or Sulfinpyrazone

Caution is advised in the administration of bismuth subsalicylate to patients taking medication for diabetes (possible enhanced hypoglycemic effect when given with salicylates) or patients taking aspirin (may increase the risk of salicylate toxicity), probenecid, or sulfinpyrazone (uricosuric effects of probenecid or sulfinpyrazone may be decreased).

• Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Bismuth Subsalicylate Therapy should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to Bismuth Subsalicylate Therapy are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

• Inhibitors Of CYP450 Liver Enzymes

The simultaneous administration of Bismuth Subsalicylate Therapy and drugs that inhibit microsomal liver enzymes, such as cimetidine, may result in a prolonged half-life and decreased plasma clearance of metronidazole.

• Inducers Of CYP450 Liver Enzymes

The simultaneous administration of Bismuth Subsalicylate Therapy and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported in this situation. Monitor phenytoin concentrations during treatment with Bismuth Subsalicylate Therapy.

• Drugs That Prolong the QT interval

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

The common side effects of Bismuth subsalicylate include the following

Common side effects

● Anxiety, any loss of hearing, confusion, constipation, diarrhea, difficulty in speaking or slurred speech, dizziness or lightheadedness, Drowsiness, fast or deep breathing, headache, increased sweating, increased thirst, mental depression, muscle spasms (especially of the face, neck, and back), muscle weakness, nausea or vomiting, ringing or buzzing in ears, stomach pain, trembling, uncontrollable flapping movements of the hands (especially in elderly patients) or other uncontrolled body movements, vision problems.

• Pregnancy

Pregnancy Category D

Bismuth Subsalicylate Therapy contains bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. There are no adequate and well-controlled studies of Bismuth Subsalicylate Therapy in pregnant women. However, tetracycline can cause fetal harm when administered to a pregnant woman. The use of tetracycline during the second and third trimesters of pregnancy can also cause permanent discoloration of the teeth (yellow-gray, brown) and possibly inhibit bone development. Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in newborn animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

• Nursing Mothers

Bismuth Subsalicylate Therapy contains bismuth subsalicylate, metronidazole, and tetracycline hydrochloride. Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in animal studies, a decision should be made whether to discontinue nursing or to discontinue metronidazole, considering the importance of the therapy to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of Bismuth Subsalicylate Therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

• Pediatric Use

The safety and effectiveness of Bismuth Subsalicylate Therapy in pediatric patients infected with H. pylori have not been established.

• Geriatric Use

Clinical studies of Bismuth Subsalicylate Therapy did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, elderly patients may have a greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapies. Bismuth subsalicylate, a component of Bismuth Subsalicylate Therapy, is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, additional monitoring may be required.

The main concern of an acute bismuth subsalicylate (BSS) overdose focuses on the salicylate burden and not on bismuth, since less than 1% of the bismuth is normally absorbed. Each 262.4-mg tablet of BSS contains an amount of salicylate comparable to approximately 130 mg aspirin. Acute ingestion of less than 150 mg/kg of aspirin (i.e., less than one tablet of bismuth subsalicylate per kilogram of body weight) is not expected to lead to toxicity. Mild to moderate toxicity may result from the ingestion of 150 to 300 mg/kg, while severe toxicity may occur from ingestions over 300 mg/kg. Salicylate intoxication presents a complex clinical picture. Multiple respiratory and metabolic effects result in fluid, electrolyte, glucose, and acid-base disturbances. Initial symptoms of salicylate toxicity include hyperpnea, nausea, vomiting, tinnitus, hyperpyrexia, lethargy, tachycardia, and confusion. In severe cases, these symptoms may progress to severe hyperpnea, convulsions, pulmonary or cerebral edema, respiratory failure, cardiovascular collapse, coma, and death.

Treatment

There is no specific antidote for salicylate poisoning. If there are no contraindications, vomiting should be induced as soon as possible with syrup of ipecac, or gastric lavage should be instituted, provided that no more than one hour has elapsed since ingestion. Activated charcoal and a cathartic may be administered as primary decontamination therapy in those cases where greater than one hour has elapsed since ingestion, or to further decontaminate the gastrointestinal tract in those who have already received ipecac or gastric lavage. Plasma salicylate levels may be useful; a common nomogram can be used to help predict the severity of intoxication. Supportive and symptomatic treatment should be provided, with emphasis on correcting fluid, electrolyte, blood glucose, and acid-base disturbances. Elimination may be enhanced by urinary alkalinization, hemodialysis, or hemoperfusion. Since hemodialysis aids in correcting acid-base disturbances, this method may be preferred over hemoperfusion.

Pharmacodynamic

Bismuth subsalicylate is an antacid and antimicrobial, gastroprotective, anti-secretory, and anti-inflammatory actions. It works to reduce the severity and incidence of flatulence and diarrhea and consequently relieving gastrointestinal discomfort. In one study, bismuth subsalicylate was prevented traveler's diarrhea with a protection rate >60%. Organobismuth compounds, formed by the breakdown of bismuth subsalicylate in the gastrointestinal tract, inhibit the growth of Helicobacter pylori and other bacteria implicated in gastrointestinal disorders, and some fungi. In one study, bismuth subsalicylate was shown to eradicate up to 90% of H. pylori infections when used as part of a quadruple therapy regimen containing a proton pump inhibitor, tetracycline, and metronidazole. Bismuth subsalicylate exhibited antimicrobial activity against Clostridium difficile, enterotoxigenic Escherichia coli O157:H7, norovirus, and other common enteric pathogens such as Salmonella and Shigella.

Pharmacokinetics

• Absorption

Less than 1% of bismuth from oral doses of bismuth subsalicylate is absorbed from the gastrointestinal tract into the systemic circulation.

• Distribution

Absorbed bismuth is distributed throughout the body. Bismuth is highly bound to plasma proteins (> 90%).

• Metabolism and Excretion

Bismuth has multiple disposition half-lives with an intermediate half-life of 5 to 11 days and a terminal half-life of 21 to 72 days. Elimination of bismuth is primarily through urinary and biliary routes with a renal clearance of 50 ± 18 mL/min.

• https://go.drugbank.com/drugs/DB01294
• https://www.rxlist.com/helidac-drug.htm#clinpharm
• https://reference.medscape.com/drug/kaopectate-pepto-bismol-bismuth-subsalicylate-342037
• https://medlineplus.gov/druginfo/meds/a607040.html#side-effects
• https://www.drugs.com/dosage/bismuth-subsalicylate.html
• https://www.uptodate.com/contents/bismuth-subsalicylate-drug-information#F27758326