OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Bismuth – Generic, Helidac®, Pylera®

DRUG CLASS

Trace Elements and Metals

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Bismuth Subsalicylate	14882-18-9	C7-H6-Bi-O

ANNOTATED BIBLIOGRAPHY

References updated: 03 April 2024

Abbreviations used: H. pylori, Helicobacter pylori.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999; bismuth is not discussed).
• Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.

  (Textbook on hepatotoxicity; bismuth is not discussed).
• Byrns MC, Penning TM. Treatment of metal exposure. Environmental toxicology: carcinogens and heavy metals. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1311-5.

  (Textbook of pharmacology and therapeutics).
• Stokes JH, Ruedemann R, Lemon WS. Epidemic infectious jaundice and its relation to the therapy of syphilis. Arch Intern Med 1920; 26: 521-543. Not in PubMed.

  (Between 1916 and 1920, there were 70 cases of jaundice arising during arsphenamine therapy of syphilis at the Mayo Clinic, but the frequency increased markedly during that time [1000-fold] suggesting an epidemic of hepatitis rather than hepatitis from therapy, an idea which was also supported by a lack of uniform latency to onset after starting therapy and lack of recurrence when therapy was resumed as well as the similarity of symptoms [particularly prodromal symptoms of fever, arthritis, and rash], laboratory tests, and timing between jaundice in epidemics occurring concurrently in Minnesota).
• Nomland R, Skolnik EA, McLellan LL. Jaundice from bismuth compounds used in the therapy of syphilis. JAMA 1938; 11; 19-21. Not in PubMed.

  (Among 75 cases of jaundice occurring during therapy of syphilis, 32 were attributed to bismuth subsalicylate, after 11 to more than 30 injections, beginning within 6 weeks of the last dose, ten having received bismuth only, the remainder also receiving arsphenamine. The authors state that the injury is indistinguishable from “catarrhal jaundice” [acute viral hepatitis] and in several cases bismuth was restarted without recurrence of jaundice, factors that suggest that the injury was due to acute hepatitis B or C transmitted by inadequately sterilized reusable syringes or needles).
• Wolllmann J. Acute necrosis of the liver following sodium bismuth thioglycolate administration. Am J Syph Gonorrhea Vener Dis 1940; 29: 330-336. Not in PubMed.

  (Two case reports of newborns developing acute hepatic necrosis and fulminant liver failure after injections of bismuth for treatment of syphilis, one shortly after the first injection and the other after 10 injections over almost a year of therapy).
• Kulchar HV, Reynolds WJ. Bismuth hepatitis. JAMA 1942; 120: 343-346. Not in PubMed.

  (Among 1032 inmates at San Quentin receiving treatment for syphilis between 1936 and 1942, 144 developed jaundice during bismuth therapy [typically after 4-8 of the 60 injections required]; all were male, 103 white, ages 19 to 58 years, 117 also received arsenicals).
• Burns R, Thomas DW, Barron VJ. Reversible encephalopathy possibly associated with bismuth subgallate ingestion. Br Med J. 1974;1(5901):220-3. [PMC free article: PMC1633100] [PubMed: 4818163]

  (Description of 5 patients who developed neurologic symptoms of tremulousness, confusion, ataxia, and myoclonic jerks, 6 months to 6 years after colorectal cancer surgery and long term intermittent treatment with oral bismuth subgallate; one patient died and one redeveloped symptoms upon restarting bismuth).
• Lowe DJ. Adverse effects of bismuth subgallate. A further report from the Australian Drug Evaluation Committee. Med J Aust 1974; 2: 664-6. Not in PubMed.4453225 [PubMed: 4453225]

  (Summary of 29 patients who developed bismuth encephalopathy between 1966 and 1972 in Australia after treatment with oral bismuth subgallate daily for a variable period [weeks to years] as a means of controlling the consistency and odor of stool in patients with ileostomy and colostomy, most resolving within 1-3 months of stopping bismuth, but some with persistent neurologic symptoms; no mention of serum aminotransferase elevations or hepatotoxicity).
• Henderson IWD. Warning against products containing bismuth subsalicylate. Can Med Assoc J. 1980;123:848. [PMC free article: PMC1704921] [PubMed: 7437988]

  (Expression of caution in using bismuth subsalicylate because of detectable levels of salicylate, which might be problematic in patients receiving anticoagulants or other salicylates).
• Hasking GJ, Duggan JM. Encephalopathy from bismuth subsalicylate. Med J Aust. 1982;2:167. [PubMed: 7132858]

  (60 year old man with intermittent diarrhea developed inappropriate behavior, confusion, muscle twitching, and incontinence after using bismuth subsalicylate for several years with a blood bismuth level of 72 μg/L [normal less than 5 μg/L] and who recovered completely within a month of stopping bismuth).
• Bianchi Porro G, Lazzaroni M, Cortvriendt WR. Maintenance therapy with colloidal bismuth subcitrate in duodenal ulcer disease. Digestion. 1987;37 Suppl 2:47-52. [PubMed: 3305118]

  (Among 39 adults with healed duodenal ulcer treated with daily bismuth subcitrate, there were mild side effects only and no patient developed bismuth encephalopathy or significant elevations in bismuth levels).
• Bradley B, Singleton M, Lin Wan Po A. Bismuth toxicity--a reassessment. J Clin Pharm Ther. 1989;14:423-41. [PubMed: 2693474]

  (Extensive review of the toxicity of bismuth salts, focusing upon subsalicylate and subcitrate, including melanosis, oral discoloration, skeletal problems, nephrotoxicity, hepatotoxicity, and neurotoxicity, mentions 180 published cases of liver toxicity, 140 of which were also exposed to arsphenamine and commenting that other hepatotoxins could account for all the cases reported).
• Dunk AA, Prabhu U, Tobin A, O'Morain C, Mowat NA. The safety and efficacy of tripotassium dicitrato bismuthate (De-Nol) maintenance therapy in patients with duodenal ulceration. Aliment Pharmacol Ther. 1990;4:157-62. [PubMed: 2104081]

  (Among 79 adults with healed duodenal ulcers treated with maintenance bismuth subcitrate [120 mg daily] for up to 12 months, therapy was well tolerated, there were no discontinuations for adverse events, and routine biochemistry tests showed no evidence of hepatotoxicity).
• Jungreis AC, Schaumburg HH. Encephalopathy from abuse of bismuth subsalicylate (Pepto-Bismol). Neurology. 1993;43:1265. [PubMed: 8192812]

  (67 year old woman developed tremor, confusion, and intermittent delirium, 18 months after starting use of large doses of an oral solution of bismuth subsalicylate [Pepto-Bismol] for episodes of abdominal pain, plasma bismuth was 36 μg/L six weeks after stopping bismuth, and the neurologic symptoms resolving 6 months later).
• Youngman L, Harris S. BIPP madness; an iatrogenic cause of acute confusion. Age Ageing. 2004;33:406-7. [PubMed: 15082418]

  (81 year old man developed acute confusion two days after nasal packing and surgery for epistaxis which was found to be attributable to bismuth toxicity, the source being bismuth iodoform paraffin paste [BIPP] used for nasal packing; serum “biochemistry” tests were reported to be normal).
• Ford AC, Malfertheiner P, Giguere M, Santana J, Khan M, Moayyedi P. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis. World J Gastroenterol. 2008;14:7361-70. [PMC free article: PMC2778120] [PubMed: 19109870]

  (Systematic review of 35 controlled trials of bismuth containing regimens [for 7 to 56 days] for eradication of Helicobacter pylori in 4763 patients found no difference in overall adverse event rates, individual adverse event rates, or rates of discontinuations for adverse events; no mention of liver injury or hepatotoxicity).
• Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F; Pylera Study Group. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377(9769):905-13. Erratum in: Lancet. 2011 Nov 19;378(9805):1778. [PubMed: 21345487]

  (Controlled trial of quadruple [with bismuth] vs triple therapy [omeprazole and two antibiotics] for eradication of H. pylori infection in 440 adults demonstrated superiority of the quadruple regimen [80% vs 55%], with no difference in total and serious adverse event rates and no discontinuations for liver related events; bismuth levels increased but all were well below toxic levels and fell after stopping).
• Delchier JC, Malfertheiner P, Thieroff-Ekerdt R. Use of a combination formulation of bismuth, metronidazole and tetracycline with omeprazole as a rescue therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther. 2014;40:171-7. [PubMed: 24863854]

  (Among 49 adults with H. pylori infection who had failed a course of triple therapy and were treated with quadruple therapy using bismuth, metronidazole, tetracycline, and omeprazole for 10 days, the eradication rate was 95% and adverse event rate 67%, but only one patient discontinued therapy early and “no clinically significant changes in laboratory tests were noted”).
• Borbinha C, Serrazina F, Salavisa M, Viana-Baptista M. Bismuth encephalopathy- a rare complication of long-standing use of bismuth subsalicylate. BMC Neurol. 2019;19:212. [PMC free article: PMC6714398] [PubMed: 31464594]

  (44 year old woman developed abnormal behavior, confusion, postural instability, and myoclonic jerks having used bismuth subsalicylate [Pepto-Bismol] irregularly for 20 years for gastrointestinal complaints [serum bismuth 260 μg/L, liver tests normal], slowing improving as serum levels of bismuth fell and was back to baseline function 3 months later; finding of greyish discoloration of teeth gradually resolving).
• Silva C, Merim S, Sevivas R, Mota J, Leitão A. Bismuth subcitrate, metronidazole and tetracycline - a rare cause of drug-induced liver injury. Eur J Case Rep Intern Med. 2023;10:004119. [PMC free article: PMC10705836] [PubMed: 38077712]

  (37 year old man with H. pylori infection developed nausea, abdominal pain, and fever 5 days after starting triple therapy with bismuth subcitrate, metronidazole and tetracycline [bilirubin 3.0 mg/dL, ALT 839 U/L, Alk P 136 U/L, INR 1.4], which resolved within 4 weeks of stopping therapy, the cause being unclear but perhaps due to metronidazole).
• Moss SF, Shah SC, Tan MC, El-Serag HB. Evolving concepts in Helicobacter pylori management. Gastroenterology. 2024;166:267-283. [PMC free article: PMC10843279] [PubMed: 37806461]

  (Review of current recommendations for management of H. pylori infection states: “retrospective studies of H. pylori eradication, although sparse, suggest that bismuth-quadruple therapy for 10-14 days is likely the current best choice for empiric therapy in the U.S.”; no mention of adverse events, ALT elevations, or hepatotoxicity).