S691
Pharmacology of Bismuth-Containing Compounds John Russell Lambert
From the Department of Medicine, Prince Henry's Hospital, Melbourne, Victoria, Australia
Bismuth compounds have been used for more than two centuries. A review of the modes of action, pharmacokinetics, and toxicity of two commonly used compounds, colloidal bismuth subcitrate and bismuth subsalicylate, is presented. In humans bismuth toxicity is unlikely when therapeutic doses ofthese compounds are administered for the appropriate duration. The recent use of bismuth compounds to eradicate infection with Helicobacter pyloriand to prevent travelers' diarrhea has resulted in scientific reevaluation of these agents.
Bismuth compounds have been used as medicinal agents for more than two centuries, with the first recorded medical use in 1785. Early applications included the use of local demulcent and protective activities in the skin and gastrointestinal tract to aid the healing of ulcers [1-7] as well as to treat and prevent acute diarrhea [8] (table 1). Bismuth salts have also been used as a contrast material in gastrointestinal radiology. All of these uses are dependent on local effects. In addition, however, the systemic effects of bismuth have led to its use in the treatment of syphilis and hypertension. Many oral preparations of bismuth have been used. The various preparations appear to differ in clinical efficacy as well as pharmacokinetics. The inorganic salts used have included subnitrate, subcarbonate, subgallate, tartrate, and the subsalicylate. The commercial preparations have generally been available over the counter and have often contained other compounds in addition to the bismuth salt; several such preparations are still available in some countries. The two bismuth compounds most commonly used worldwide-colloidal bismuth subcitrate (De-Nol; Gist Brocades, Delft, The Netherlands) and bismuth subsalicylate (Pepto-Bismol; The Procter & Gamble Company, Cincinnati, Ohio)-will be considered in this review. Colloidal bismuth subcitrate (CBS) has been used successfully in the treatment of both gastric [1-3] and duodenal [4-7] ulcer disease. This preparation has proved as effective as the histamine Hz antagonists in the treatment of gastric and duodenal ulcers and has been associated with lower relapse rates after cessation of therapy. The lower relapse rate after initial healing with CBS has been attributed to its ability to eradicate Helicobacter (Campylobacter) pylori [9-11]and to moderate the gastroduodenitis associated with infection by this organism [11-14]. Long-term eradication of H. pylori is more likely when CBS is administered along with antibiotics [15].
Reprints and correspondence: Dr. John R. Lambert, Department of Medicine, Prince Henry's Hospital, St. Kilda Road, Melbourne, Victoria, Australia 3004. Reviews of Infectious Diseases 1991;13(SuppI8):S691-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111304-0006$02 .00
Bismuth subsalicylate (BSS) is effective in the prevention of travelers' diarrhea [16] and the treatment of dyspepsia.
Mode of Action Both CBS [17-29] and BSS [30-35] have many activities within the gastrointestinal tract. The modes of action of the two compounds are compared in table 2. Many properties are shared by these agents. After 4-8 weeks of therapy, longterm eradication of H. pylori is documented in 20%-32 % of persons given CBS [9-14] and in 500 p,g/L at the time of presentation [58, 64]. The lack of relation between clinical illness and blood concentrations noted in some case reports [61, 65] can be accounted for by one or more of the following factors: substantial interindividual variation in susceptibility to bismuth neurotoxicity; inadequate assessment of bismuth levels in blood, with samples often taken late after presentation; and frequent discontinuation of bismuth intake by patients before hospitalization. The interpretation of "Hillemand[66] safetylevels" (50-100 p,g ofbismuth/L) as a warning sign of toxicity is not justified by current knowledge. This range was based on early French studies in which the accuracy of the analytical methods used was uncertain and the times when blood samples were obtained were not specified. As would be anticipatedfrom the pharmacokineticsof CBS, no toxic effects in persons taking the recommended dosage for the recommendeddurationhavebeen reported. The steadystate plasma concentrations of bismuth with standard doses of any preparation of CBS were
Pharmacology of Bismuth-Containing Compounds John Russell Lambert
From the Department of Medicine, Prince Henry's Hospital, Melbourne, Victoria, Australia
Bismuth compounds have been used for more than two centuries. A review of the modes of action, pharmacokinetics, and toxicity of two commonly used compounds, colloidal bismuth subcitrate and bismuth subsalicylate, is presented. In humans bismuth toxicity is unlikely when therapeutic doses ofthese compounds are administered for the appropriate duration. The recent use of bismuth compounds to eradicate infection with Helicobacter pyloriand to prevent travelers' diarrhea has resulted in scientific reevaluation of these agents.
Bismuth compounds have been used as medicinal agents for more than two centuries, with the first recorded medical use in 1785. Early applications included the use of local demulcent and protective activities in the skin and gastrointestinal tract to aid the healing of ulcers [1-7] as well as to treat and prevent acute diarrhea [8] (table 1). Bismuth salts have also been used as a contrast material in gastrointestinal radiology. All of these uses are dependent on local effects. In addition, however, the systemic effects of bismuth have led to its use in the treatment of syphilis and hypertension. Many oral preparations of bismuth have been used. The various preparations appear to differ in clinical efficacy as well as pharmacokinetics. The inorganic salts used have included subnitrate, subcarbonate, subgallate, tartrate, and the subsalicylate. The commercial preparations have generally been available over the counter and have often contained other compounds in addition to the bismuth salt; several such preparations are still available in some countries. The two bismuth compounds most commonly used worldwide-colloidal bismuth subcitrate (De-Nol; Gist Brocades, Delft, The Netherlands) and bismuth subsalicylate (Pepto-Bismol; The Procter & Gamble Company, Cincinnati, Ohio)-will be considered in this review. Colloidal bismuth subcitrate (CBS) has been used successfully in the treatment of both gastric [1-3] and duodenal [4-7] ulcer disease. This preparation has proved as effective as the histamine Hz antagonists in the treatment of gastric and duodenal ulcers and has been associated with lower relapse rates after cessation of therapy. The lower relapse rate after initial healing with CBS has been attributed to its ability to eradicate Helicobacter (Campylobacter) pylori [9-11]and to moderate the gastroduodenitis associated with infection by this organism [11-14]. Long-term eradication of H. pylori is more likely when CBS is administered along with antibiotics [15].
Reprints and correspondence: Dr. John R. Lambert, Department of Medicine, Prince Henry's Hospital, St. Kilda Road, Melbourne, Victoria, Australia 3004. Reviews of Infectious Diseases 1991;13(SuppI8):S691-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111304-0006$02 .00
Bismuth subsalicylate (BSS) is effective in the prevention of travelers' diarrhea [16] and the treatment of dyspepsia.
Mode of Action Both CBS [17-29] and BSS [30-35] have many activities within the gastrointestinal tract. The modes of action of the two compounds are compared in table 2. Many properties are shared by these agents. After 4-8 weeks of therapy, longterm eradication of H. pylori is documented in 20%-32 % of persons given CBS [9-14] and in 500 p,g/L at the time of presentation [58, 64]. The lack of relation between clinical illness and blood concentrations noted in some case reports [61, 65] can be accounted for by one or more of the following factors: substantial interindividual variation in susceptibility to bismuth neurotoxicity; inadequate assessment of bismuth levels in blood, with samples often taken late after presentation; and frequent discontinuation of bismuth intake by patients before hospitalization. The interpretation of "Hillemand[66] safetylevels" (50-100 p,g ofbismuth/L) as a warning sign of toxicity is not justified by current knowledge. This range was based on early French studies in which the accuracy of the analytical methods used was uncertain and the times when blood samples were obtained were not specified. As would be anticipatedfrom the pharmacokineticsof CBS, no toxic effects in persons taking the recommended dosage for the recommendeddurationhavebeen reported. The steadystate plasma concentrations of bismuth with standard doses of any preparation of CBS were
