Continuing Education Activity

Bismuth subsalicylate is a medication used to manage and treat gastrointestinal discomfort and traveler's diarrhea. It is in the salicylates class of drugs. This activity reviews the indications, action, and contraindications for bismuth subsalicylate as a valuable agent in treating and managing gastrointestinal discomfort and traveler's diarrhea.

Objectives:

• Describe the mechanism of action of bismuth subsalicylate.
• Outline the potential adverse effects of bismuth subsalicylate.
• Review the appropriate monitoring for patients using bismuth subsalicylate.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance bismuth subsalicylate and improve outcomes.

Indications

Bismuth subsalicylate (BSS) has been around for over 100 years and was first FDA approved in 1939. It was created prior to the practice of hygiene and sanitation for the cure of cholera infections. BSS has provided healthcare professionals with an alternative option to antimicrobials for the treatment of nausea and diarrhea. The primary indications of BSS involve gastrointestinal conditions and traveler's diarrhea.[1]

Diarrhea/Dyspepsia

The FDA-approved indications of BSS are for treating diarrhea, heartburn, indigestions, nausea, and stomach upset. BSS is effective in situations where patients are experiencing mild gastrointestinal discomfort, as it reduces the severity and incidence of flatulence and diarrhea.[2] In comparison to a placebo, BSS was able to provide greater and faster relief in patients with mild, moderate, and severe symptoms. [3] BSS can be found over the counter and does not require a prescription; as such, it has become a preferred self-treatment option for mild diarrhea, replacing the need for an antimicrobial.[4][5]

Helicobacter Pylori 

One off-label indication for BSS use is to eradicate Helicobacter pylori (H. pylori) gastrointestinal tract infection.[6][7][8] When used as part of a quadruple therapy regimen containing a proton pump inhibitor, tetracycline, and metronidazole, the research has found that BSS eradicated up to 90% of H. pylori infections.[8][9]

Traveler's Diarrhea

Another off-label indication for BSS is for the prophylaxis and treatment of traveler's diarrhea. In developing countries, traveler's diarrhea affects at least 20% to more than 50% of tourists.[4] BSS demonstrated effectiveness in the acute treatment of traveler's diarrhea in patients with mild symptoms.[10] A review article that included four different studies with a combination of N=2500 patients found that BSS was significantly superior to placebo for the treatment of travelers' diarrhea. Furthermore, BSS decreased stool frequency and time to symptom relief in comparison to placebo.[11]

BSS may also be used to prevent traveler's diarrhea. However, its prophylactic efficacy was less than antimicrobials (62% versus 80%, respectively).[12] The frequency in the administration of BSS in multiple doses (three to four times daily) may compromise patient adherence and, as such, affect the rates of prevention of traveler's diarrhea. Although not particularly common, bismuth subsalicylate has also demonstrated effectiveness for the treatment of cholera in children.[13]

Mechanism of Action

Bismuth subsalicylate (BSS) exhibits many of its properties due to its formulation as an insoluble salt of salicylic acid and trivalent bismuth. The mechanism of action through which BSS works is complex. In the stomach, BSS hydrolyzes into two compounds, bismuth and salicylic acid.[14] The salicylate compound is almost completely absorbed into the bloodstream, while bismuth salt is minimally absorbed.[15] The bismuth that remains in the gastrointestinal tract forms other bismuth salts. These bismuth salts contain bactericidal and antimicrobial activity and prevent bacteria from binding and growing on the mucosal cells of the stomach. This is the mechanism by which BSS helps eradicate H. pylori.[14] Furthermore, the prevention of bacterial binding to the mucosal cells provides many benefits, including preventing intestinal secretion, promoting fluid absorption, reducing inflammation, and promoting the healing of any present ulcer in the stomach.[16]

It appears as though BSS does not alter the normal flora of the stomach; however, its antimicrobial and antisecretory properties play a significant role in combating diarrhea. The antidiarrheal effect of BSS is most likely due to: 

• The reduction in prostaglandin formation, as BSS inhibits cyclooxygenase. Prostaglandin induces inflammation and hypermotility.
• The stimulation of reabsorption of fluids, sodium, and chloride - this action helps decrease fluid loss.[17]
• The inhibition of intestinal secretions. 

While, in peptic ulcer disease, the likely mechanism of BSS involves its cytoprotective and demulcent activity. In H. pylori specifically, BSS blocks the adhesion of the bacteria to the gastric epithelial cells. Additionally, BSS inhibits H. pylori's enzyme activities, including phospholipase, protease, and urease.[18][19]

Administration

Bismuth subsalicylate is administered orally and requires storage at room temperature. BSS is available in either suspension or tablet form. Patients (adults and children) should be advised to shake the suspension well before use and to utilize the enclosed dosage cup. The chewable tablets may be dissolved in the mouth or chewed and swallowed. However, non-chewable tablets should be swallowed whole and taken with water. The proper recommended dosage depends on the indication and the age of the patient. Of note, data for BSS use in pediatric patients less than 12 years old is limited. 

Diarrhea/Dyspepsia

• Adult dose: 524 mg every 30 minutes to 1 hour as needed (regular strength) or 1050 mg every 60 minutes (maximum strength) for up to 2 days (maximum dose of approximately 4,200 mg)
• Pediatric dose:
  • Adolescents ≥ 12 years: same as adult dosing  
  • 9 to <12 years: 262 mg every 30 minutes to 1 hour as needed 
  • 6 to 9 years: 175 mg every 30 minutes to 1 hour as needed
  • 3 to <6 years: 87 mg every 30 minutes to 1 hour as needed 

Helicobacter Pylori [20]

• Adult dose: 300 mg four times daily as part of quadruple combination therapy for 10 to 14 days[9][21]
• Pediatric dose: 4 mg/kg twice daily for 10 to 14 days as part of a triple or quadruple therapy[21][20]

Traveler's Diarrhea

• Prophylaxis for traveler's diarrhea adults dose (off-label use): 524 mg four times daily with meals and at bedtime during the time of risk (recommendation is limited for trips less than two weeks of duration)[22][23]
• Treatment of traveler's diarrhea adults dose (off-label use): 524 mg every 30 minutes to 1 hour as needed (maximum of 8 doses/24 hours)[24]

Adverse Effects

The common adverse effects associated with the administration of bismuth subsalicylate are nausea, bitter taste, diarrhea, and dark/black stools.[25] Although not common, bismuth toxicity can result from the overconsumption of bismuth subsalicylate over an extended period of time and can result in the blackening of the tongue and teeth, fatigue, mood changes, and deterioration of mental status.[26] 

Bismuth subsalicylate can be fatal in very rare circumstances and can lead to neurotoxicity.[27][26] Other adverse effects with an unknown frequency of BSS include hearing loss or tinnitus, muscle spasms or weaknesses, anxiety, confusion, depression, headaches, and potentially slurred speech.

Contraindications

In patients with certain medical conditions, bismuth subsalicylate should not be used. BSS should be avoided in: 

• Patients undergoing oral treatments for gastric and intestinal conditions with anticoagulants, sulfinpyrazone, probenecid, methotrexate, or any medication with high salicylate concentrations
• Patients with gastrointestinal ulceration or hemophilia
• Patients with bleeding problems or bloody/black stools before administration of BSS
• Children less than 12 years of age
  • There is limited data for BSS use in children under the age of 12 years old; other treatment options may be preferable.
• Children or adolescents with flu-like symptoms
  • Although not yet reported, BSS may potentially cause Reye's syndrome in pediatrics or adolescents recovering from influenza or varicella. 
• Patients sensitive or allergic to salicylates
  • In patients who have demonstrated sensitivity toward aspirin, it is advisable not to use bismuth subsalicylate.[28]

For patients with any of the listed conditions, the suggestion is that they use alternative treatment options. Patients should be cautious in using bismuth subsalicylate when traveling to countries where malaria is prevalent, as it can decrease the absorption of doxycycline, which is an effective antimicrobial for prophylaxis against malaria.[5]

Monitoring

Before administering bismuth subsalicylate (BSS), the recommendation is to assess the patient's active medication therapies and history of allergies. Dose adjustment of BSS or alternate treatment may be necessary depending on the patient's medical history. Patients should be counseled on the proper administration of BSS and what to do in cases where diarrhea symptoms persist.

The therapeutic efficacy of BSS is demonstrated by the reduction in the number of unformed stools and the relief of symptoms. Most patients should see a positive therapeutic response within four hours of the ingestion of BSS. Toxicity of BSS is rare; as such, salicylate plasma concentrations do not need to be monitored.[5] In the cases where toxicity is suspected, follow-up monitoring at least 12 hours after the ingestion of salicylate products is recommended.

Toxicity

The most concerning adverse effect of bismuth subsalicylate (BSS) is salicylate toxicity. Although quite rare, bismuth toxicity can occur in patients. It primarily occurs in patients who have taken bismuth subsalicylate inappropriately, whether through an overdose or for extended periods of time.[29] Symptoms of bismuth toxicity include impaired cognition, tremors, lethargy, somnolence, insomnia, delirium, myoclonus, seizures, depressed mood, anxiety, and a depressed mood.[30] If a patient is experiencing bismuth toxicity, they should discontinue BSS use and seek medical attention. Fortunately, there is little evidence to suggest that bismuth subsalicylate can be fatal, although there have been a few reported cases.[28]

Toxicity is generally seen in patients who ingest more than 150 mg/kg of salicylates (or > 6.5 g of aspirin equivalent). There are no specific antidotes for salicylate toxicity. However, the management of mild to moderate toxicity generally includes supportive care with intravenous fluids. If the patient presents within 2-hours of ingestion of BSS, decontamination with activated charcoal is strongly recommended. Salicylate absorption can be delayed; as such, activated charcoal may also be considered after 2-hours of ingestion if the patient is in a normal mental state. It is recommended to check a salicylate concentration every 1 to 2 hours until a decline is observed. If the salicylate concentration is more than 30 mg/dL, the healthcare team should consider urine alkalization.

In more severe cases and with the presence of altered mental status and metabolic acidosis, hemodialysis may be an option. If the patient is not able to maintain their airway and intubation is required, precautions should be taken to avoid severe acidosis. It is recommended to closely follow up with arterial blood gases and maintain the pre-intubation minute ventilation and low PCO2. Other laboratory parameters that are recommended to be collected include hepatic panel, INR/PTT, CBC, electrolytes, and serum creatinine (renal function tests).

Enhancing Healthcare Team Outcomes

In the United States, bismuth subsalicylate (BSS) is an over-the-counter (OTC) product.[25] Even though this medication is available without a prescription, the interprofessional healthcare team needs to be cognitive of the proper use of BSS and coordinate care to educate patients and monitor both efficacy and toxicity. Pharmacists can identify any drug-drug interactions with BSS and recommend the findings to both providers and patients. Nurses and pharmacists can play a significant role in providing patient education about the proper use of BSS and informing the patient about common adverse effects. For instance, patients should be aware that the darkening of the stool or tongue with the use of BSS is temporary and harmless. However, patients should contact a healthcare provider before ingesting BSS if they develop fever or mucus in the stool. Furthermore, patients should discontinue the use of BSS if:

• Their symptoms last for more than 14 days
• Their symptoms worsen
• They do not have relief of diarrhea after two days of use
• They develop a fever
• They experience hearing loss or tinnitus[16]

Finally, in the cases where toxicity is suspected, a consult to a clinical toxicologist or a poison control center is encouraged to help manage the patient appropriately.