Continuing Education Activity

This educational activity focuses on bismuth subsalicylate's applications in managing gastrointestinal discomfort and traveler's diarrhea. The drug's mechanism of action, potential adverse reactions, and contraindications will be discussed. By also exploring bismuth subsalicylate's pharmacokinetics, optimal administration methods, and necessary monitoring protocols, this program aims to enhance professionals' proficiency in clinical toxicology related to the medication. The goal of this program is to furnish healthcare professionals with the requisite expertise to administer bismuth subsalicylate optimally. By providing evidence-based information, this discussion facilitates informed decision-making, enabling practitioners to tailor treatment strategies to individual patient needs. By understanding bismuth subsalicylate's intricacies, healthcare professionals can mitigate adverse reactions, optimize dosages, and deliver precise, safe, and individualized care.

Objectives:

• Evaluate the mechanism of action of bismuth subsalicylate.

• Assess the potential adverse effects of bismuth subsalicylate.

• Identify the appropriate monitoring for patients using bismuth subsalicylate.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from bismuth subsalicylate therapy.

Indications

FDA-Approved Indications

Bismuth subsalicylate (BSS) has been available to the public for more than 100 years and was first FDA-approved in 1939. BSS was created before widespread hygiene and sanitation practices to cure cholera infections. This medication has provided healthcare professionals with an alternative option to antimicrobials for the treatment of nausea and diarrhea. The primary indications of BSS include gastrointestinal conditions and traveler's diarrhea.[1]

Diarrhea/Dyspepsia

The FDA-approved indications of BSS include 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] Compared to placebo, BSS was able to provide greater and faster relief in patients with mild, moderate, and severe symptoms.[3] BSS can be purchased over the counter and does not require a prescription; it has become a preferred self-treatment option for mild diarrhea, replacing the need for an antimicrobial.[4][5]

Off-Label Uses

Helicobacter Pylori 

One off-label indication for BSS is the management of Helicobacter pylori (H. pylori) gastrointestinal tract infection.[6][7][8] Studies have shown that when used as part of a quadruple therapy regimen containing a proton pump inhibitor, tetracycline, and metronidazole, BSS eradicated up to 90% of H. pylori infections.[8][9] The American Gastroenterological Association (AGA) suggests bismuth quadruple therapy as a first-line treatment option. This therapy is administered for 10 to 14 days and includes a proton pump inhibitor (PPI), bismuth, tetracycline, and nitroimidazole. This therapy combination is recommended for patients with previous macrolide exposure or who are allergic to penicillin.[9]

Traveler's Diarrhea

Another off-label indication for BSS is prophylaxis and treatment of traveler's diarrhea. In developing countries, traveler's diarrhea affects 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 4 studies with a combined 2,500 patients found that BSS was significantly superior to placebo for treating travelers' diarrhea. Additionally, BSS decreased stool frequency and time to symptom relief compared 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 of administering BSS in multiple doses (3 to 4 times daily) may decrease patient adherence and affect prevention rates of traveler's diarrhea. Although uncommon, bismuth subsalicylate has also demonstrated effectiveness in the treatment of cholera in children.[13]

For individuals diagnosed with symptomatic microscopic colitis who cannot undergo budesonide therapy, the American Gastroenterological Association (AGA) recommends treatment with bismuth salicylate as an alternative to no treatment, with the goal of inducing clinical remission.[14]

Mechanism of Action

Bismuth subsalicylate (BSS) exhibits many 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 2 compounds, bismuth and salicylic acid.[15] The salicylate compound is almost completely absorbed into the bloodstream, while bismuth salt is minimally absorbed.[16] 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.[15] Furthermore, preventing 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.[17]

BSS does not appear to 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.[18]
• The inhibition of intestinal secretions 

In peptic ulcer disease, the likely mechanism of BSS involves its cytoprotective and demulcent activity. In H. pylori infections, 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.[19][20]

Administration

Available Dosage Forms and Strengths

Bismuth subsalicylate is administered orally and requires storage at room temperature. BSS is available in suspension (262 mg/15 mL, 525 mg/15 mL, 525 mg/30 mL) or tablet form (chewable tablets 262 mg). 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. Data for BSS use in pediatric patients younger than 12 years old is limited.

Diarrhea/Dyspepsia

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

Helicobacter Pylori [21]

• Adult dose (off-label use): 300 mg 4 times daily, as part of quadruple combination therapy for 10 to 14 days [9][22]
• Pediatric dose (off-label use): 4 mg/kg twice daily for 10 to 14 days as part of a triple or quadruple therapy [22][21]

Traveler's Diarrhea

• Prophylaxis for traveler's diarrhea adults dose (off-label use): 524 mg 4 times daily with meals and at bedtime during the time of risk (recommendation is limited for trips less than 2 weeks of duration) [23][24]
• Treatment of traveler's diarrhea adult dose: 524 mg every 30 min to 1 hr as needed (maximum of 8 doses/24 hr) [25]

Specific Patient Populations

Hepatic impairment: No recommendations are provided according to the manufacturer's label.

Renal impairment: There are no recommendations provided on the drug label. Since salicylates can worsen renal function in patients depending on prostaglandins to maintain GFR, toxicity may occur at lower doses. Using the lowest effective dose for bismuth subsalicylate in the shortest possible period is recommended when clinically feasible.[26]

Pregnancy considerations: The CDC recommends against using BSS to prevent or treat traveler's diarrhea in pregnant women. 

Breastfeeding considerations: Given the potential for the infant to absorb salicylate from breast milk, it's advisable to explore alternative treatment options for BSS.[27]

Pediatric patients: Limited data is available for BSS use in children younger than 12, and other treatment options may be preferable. Adult dose recommendations are applicable for patients 12 years old or older.

Older patients: No specific recommendations are provided.

Adverse Effects

Common adverse effects associated with administering bismuth subsalicylate include nausea, bitter taste, diarrhea, and dark/black stools.[28] Although not common, bismuth toxicity can result from the overconsumption of bismuth subsalicylate over an extended period and can result in the blackening of the tongue and teeth, fatigue, mood changes, and deterioration of mental status.[29] 

Bismuth subsalicylate can lead to neurotoxicity and be fatal in rare circumstances.[30][29] 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 or adolescents with flu-like symptoms: BSS may 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.[31]

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

Monitoring

Before administering bismuth subsalicylate (BSS), it is recommended that the patient's active medication therapies and history of allergies be assessed. Depending on the patient's medical history, a dose adjustment of BSS or alternate treatment may be necessary. 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 a reduction in the number of unformed stools and the relief of symptoms. Most patients see a positive therapeutic response within 4 hours of BSS ingestion. BSS toxicity is rare; salicylate plasma concentrations do not need to be monitored.[5] In 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, which can rarely occur. This toxicity primarily occurs in patients who have taken bismuth subsalicylate inappropriately, whether through an overdose or for extended periods.[32] Symptoms of bismuth toxicity include impaired cognition, tremors, lethargy, somnolence, insomnia, delirium, myoclonus, seizures, depressed mood, anxiety, and a depressed mood.[33] If a patient is experiencing bismuth toxicity, they should discontinue BSS use and seek medical attention. There is little evidence to suggest that bismuth subsalicylate can be fatal, although there have been a few reported cases.[31]

Toxicity is generally reported 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, managing mild-to-moderate toxicity generally includes supportive care with intravenous fluids. If the patient presents within 2 hours of ingesting BSS, decontamination with activated charcoal is strongly recommended. Salicylate absorption can be delayed; activated charcoal may be administered beyond 2 hours post-ingestion if the patient is in a normal mental state. Checking the patient's salicylate concentration every 1 to 2 hours is recommended until a decline is observed. The healthcare team should consider urine alkalization if the salicylate concentration exceeds 30 mg/dL.

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

Enhancing Healthcare Team Outcomes

Bismuth subsalicylate (BSS) is an over-the-counter (OTC) product in the United States.[28] Even though this medication is available without a prescription, the interprofessional healthcare team needs to be aware 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. Clinicians, nurses, and pharmacists can play a significant role in educating patients about the proper use of BSS and informing the patient about common adverse effects. For example, patients should be aware that the darkening of the stool or tongue using BSS is temporary and harmless. However, patients should contact a healthcare provider before ingesting BSS if they develop a fever or mucus in the stool.

Patients should discontinue the use of BSS if:

• Their symptoms last for more than 14 days
• Their symptoms worsen
• Their diarrhea does not improve after 2 days of use
• They develop a fever
• They experience hearing loss or tinnitus [17]

Finally, when toxicity is suspected, a consult with a clinical toxicologist or a poison control center is encouraged to help manage the patient's condition appropriately.