Aliment Pharmacol Ther 1997 ; 11 (Suppl. 1) : 27–33.

The actions of bismuth in the treatment of Helicobacter pylori

infection
J. R. L A M B E R T* & P. M I D O L O†
* Gastrointestinal Sciences Department, Mornington Peninsula Hospital, Frankston,
and † Microbiology Department, Monash Medical Centre, Clayton, Victoria, Australia

complex and include inhibition of protein and cell wall

SUMMARY
Bismuth salts have been used in medicine for over
three centuries, particularly in the treatment of
dyspepsia. Commonly used agents include colloidal
bismuth subcitrate (CBS), bismuth subsalicylate (BSS)
and the newer ranitidine bismuth citrate (RBC). These
are safe drugs which exert local effects on the gastro-
duodenal mucosa. Gastric mucosal levels of bismuth
exceed the concentrations required to kill Helicobacter
pylori in vitro. The mechanisms of actions of bismuth
on gastrointestinal pathogens including H. pylori are
synthesis, membrane function and ATP synthesis.
Adherence of H. pylori to surface epithelial cells is also
impaired. Bismuth monotherapy is effective in vivo to
suppress H. pylori but cure rates are low. CBS, BSS and
RBC have synergistic activity with one or two
antibiotics and are effective in eradicating H. pylori.
CBS and RBC also exert other effects on the mucosa
including cytoprotective and ulcer healing properties.
In addition, RBC is effective in inhibiting gastric acid
secretion.

INTRODUCTION CHEMISTRY

Bismuth salts have been used for more than 300 years, Bismuth has an atomic number of 83 and a molecular
initially in the treatment of skin lesions and syphilis. The weight of 208.9 daltons. It has a white crystalline
use of bismuth subnitrate in the treatment of dyspepsia structure and occurs in two valencies (3­ and 5­) with
was first reported by Odier in 1786." Bismuth compounds
have been used extensively in gastroenterology (Table 1)
Table 1. Use of bismuth salts in gastroenterology
for the treatment of stomatitis, bowel dysfunction (flatu-
lence, constipation, abdominal pain), diarrhoeal illness, Bismuth compound Indication
peptic ulcer disease, non-ulcer (functional) dyspepsia,
Bismuth subnitrate Irritable colon, gastric disorders,
and more recently, H. pylori infection. A number of constipation
bismuth salts are used throughout the world and include Bismuth subgallate Improving stool consistency and
colloidal bismuth subcitrate (CBS), bismuth subsalicylate odour in colostomy and
(BSS), bismuth subnitrate and more recently ranitidine ileostomy patients
Bismuth phosphate, Various gastrointestinal disorders
bismuth citrate (RBC).
aluminate and
This review will assess the actions of bismuth salts in the subcarbonate
treatment of H. pylori infection by discussing the chem- Bismuth subsalicylate Traveller’s diarrhoea (prevention),
istry of these agents along with their pharmacology, as dyspepsia, H. pylori
well as the actions of bismuth compounds on bacteria Colloidal bismuth Gastric and duodenal ulcers,
particularly H. pylori and the gastrointestinal tract. subcitrate non-ulcer dyspepsia, H. pylori
Ranitidine bismuth Gastric and duodenal ulcers,
Correspondence to : Professor J. R. Lambert, Mornington Peninsula Hospital, citrate H. pylori
Hastings Road, Frankston 3199, Victoria, Australia.

# 1997 Blackwell Science Ltd 27

28 J. R. L A M B E RT & P . M I D O L O
% bismuth
Compound Solubility content
Bismuth subcarbonate Water insoluble 80–82.5
Bismuth subnitrate Water insoluble 72–79
Bismuth aluminate Water insoluble 54.4
Bismuth subsalicylate Water insoluble 56.5–60
Ranitidine Water soluble 50
bismuth citrate
Bismuth subcitrate* Water soluble 52.5
Bismuth subgallate Lipid soluble 46–53
* Colloidal preparation.
the trivalent most abundant and stable form in biological
systems. Various bismuth salts are derived from bismuth
nitrate, that is then hydrolysed to bismuth subnitrate.
Bismuth subnitrate then reacts in solution with soluble
basic salts to form bismuth subcarbonate, subsalicylate,
subgallate, or subcitrate. Table 2 summarizes properties
of different bismuth compounds in relation to solubility,
the per cent of bismuth content as well as absorption in
the gastrointestinal tract. Many inorganic bismuth salts
used in medicine are very poorly soluble in water, with
solubility influenced by acidity of the medium as well as
the presence of substances such as sorbitol, tartaric acid
and citric acid.# CBS forms a colloid when dissolved in
water with particles consisting of bismuth, citrate and
hydroxy groups. In gastric juice CBS precipitates best at
low pH forming bismuth oxychloride and citrate with
precipitation impared in the presence of the sulfhydryl-
containing compounds cysteine and glutathione.$ In
contrast BSS forms the insoluble bismuth oxy form in
gastric juice.
RBC is a new compound which has unique chemical
and physical properties, different to that of a mixture of
ranitidine hydrochloride and bismuth citrate.%, & Specific
differences in the physicial and chemical properties of
RBC are observed compared with the individual agents
tested alone. These include differences in x-ray difraction
and solubility.% RBC is highly soluble in an aqueous
solution with maximum solubility occurring at a pH of 4
and above. This is similar to most other bismuth salts
which are found to have a pH optimum solubility at
between pH 4 and 7 in gastric juice.
PHARMACOLOGY OF BISMUTH SALTS
Bismuth salts exert their activity in the upper gastro-
intestinal tract via local action from luminal bismuth
within the stomach and duodenum.' Thus, knowledge of
# 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11 (Suppl. 1), 27–33
Table 2. Properties of common bismuth
salts
Absorption
Very low
Very low
Very low
Very low
Very low
Low
High
Figure 1. Gastric mucosal bismuth concentrations in humans
after oral administration of three bismuth preparations."", "#
MIC ¯ minimal inhibitory concentration against 90 % of
*!
strains of H. pylori (32 ng}l).
the local pharmacology is important to enhance our
understanding of the local sites of action and uptake into
the mucosa.( Systemic pharmacokinetics is important
when considering potential toxicity of bismuth com-
pounds on various organs throughout the body. In the
stomach bismuth citrate, bismuth oxychloride, as well as
other salts are formed after oral administration of
bismuth compounds. These salts are taken up into gastric
mucus as well as binding to protein within the base of
ulcers after coming into contact with gastric juice.), *
Uptake into the gastric mucus is influenced by intra-
gastric pH. Bismuth ions in biological systems also bind
well to sulphur atoms resulting in the formation of
bismuth–thiolate complexes."!
The gastric mucosal levels of bismuth have been
measured in humans after oral ingestion of bismuth
compounds.), "", "# Bismuth levels after oral ingestion of
CBS, BSS and RBC are found to be above the minimum
inhibitory concentration for eradication of H. pylori."", "#
The results of studies are summarized in Figure 1. The
levels of bismuth within the gastric mucus and mucosa
 A C T I O N O F B I S M U T H I N T R E A T M E N T O F H. P Y L O R I I N F E C T I O N
Figure 2. Maximum plasma bismuth concentrations after a
single dose of RBC, CBS and BSS."", "#, #!
fall rapidly over a 3-h period due to the normal turnover
of mucus.""
Absorption of bismuth following oral intake of currently
used agents is very low and depends mainly on the
properties of the bismuth salt. The mechanism of bismuth
absorption therefore is not clear, although most appears
to be absorbed from the upper small intestine."$ Uptake of
bismuth into the gastric mucosa, as seen by electron
microscopy, also occurs with both CBS and RBC."%, "& The
absorption of all currently used bismuth salts is low with
less then 0.5 % of the ingested dose absorbed with RBC"'
and CBS."( The more water soluble bismuth salts,
including CBS and RBC, are better absorbed from the
gastrointestinal tract than the insoluble inorganic salts
such as bismuth subnitrate and BSS which are absorbed
in minimal amounts. Factors modifying the absorption of
bismuth include the physicochemical properties of the
drug, the formulation of the compound, as well as dietary
factors. The formulation of CBS influences the absorption,
with higher plasma bismuth concentration peaks noted
following the swallow preparation compared with the
chew tablet."), "* A diet containing a large amount of
thiol results in binding of bismuth and hence lower
absorption. Concurrent administration of antacids de-
creases absorption of bismuth. Plasma bismuth concen-
trations after CBS and RBC are very low following single
and multiple doses. After single–dose administration the
maximum plasma bismuth concentrations (Cmax) with
RBC, BSS and CBS (tablet) are less than 30 ng}ml and are
shown in Figure 2."", "#, #! After multiple dosing for 28
days the Cmax with these agents is still very low (Figure
3),"', #" being significantly less than 100 ng}ml, which is
the suggested minimum level for toxicity as described by
Hillemand.## The steady state levels of bismuth are also
very low, suggesting minimal accumulation in the body
after 28 days of therapy."', #"
# 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11 (Suppl. 1), 27–33
29
Figure 3. Mean plasma bismuth concentrations with 28-day RBC
and CBS therapy showing the maximum concentration (Cmax)
and steady state (pre last dose) levels."', #"
The absorbed bismuth binds to plasma proteins and is
distributed throughout all tissues, predominantly the
kidney and liver. Only very small amounts of bismuth are
noted in the brain and muscles, even after prolonged
exposure in experimental animals.#! The majority of
orally ingested bismuth from these compounds are
excreted in faeces.& The absorbed bismuth is excreted
rapidly in urine with most of the metal excreted within
24 h. Approximately 10 % of the absorbed bismuth
is detected in faeces presumably owing to biliary
secretion.#"
Factors that affect the pharmacokinetics of bismuth
compounds include severe renal impairment.#&, #' with
no effect of gender or ethnicity on the absorption of these
drugs. Age similarly appears to have no effect on bismuth
pharmacokinetics. Because of the suggested biliary ex-
cretion of bismuth from the body, severe liver disease
may theoretically be associated with accumulation of
bismuth.#%
A N T I-B A C T E R I A L A C T I O N S O F B I S M U T H
Bismuth salts have anti-bacterial actions against a
number of gastrointestinal tract pathogens including E.
coli, Salmonella, Shigella, Vibrio cholera, Campylobacter
jejuni, and Yersinia.#(, #) In addition, bismuth salts have
in vitro activity against Rotaviruses and other enteric
viruses.& CBS and BSS were the first bismuth compounds
shown to inhibit the growth of H. pylori in vitro. RBC
is also active against H. pylori in vitro.$!–$# Table 3
summarizes the in vitro activity of various bismuth salts
against H. pylori.&, $!–$$ The minimal inhibitory concen-
tration of bismuth to prevent the growth of 90 % of H.
pylori tested (MIC90) ranges from 4 to 32 ng}l with
the commonly used bismuth preparations including RBC.
30 J. R. L A M B E RT & P . M I D O L O

Table 3. In vitro activity of bismuth salts against H. pylori bacterial wall and periplasmic membrane are noted on
Compound MIC ng}l Reference
electron microscopic studies.$( Inhibition of a number of
*! the enzymes produced by Helicobacter including urease,
Bismuth subcitrate 4 30 catalase and lipase are observed, which may affect the
(CBS) 32 31,32
local environment for growth of the organism.$), $*
Bismuth subsalicylate 64 32
Ranitidine bismuth 16 5,33 Adherence of H. pylori to surface epithelial cells is also
citrate inhibited by bismuth compounds.%!, %" A reduction of
Bismuth subgallate 32 32 85–90 % adherence to Hela cells was observed by
Bismuth subnitrate " 128 32 preincubation of H. pylori with CBS.%" Similarly with
MIC ¯ minimum inhibitory concentration. human surface mucosal cells adhesion of H. pylori was
prevented by preincubation with CBS. Synthesis of ATP
Table 4. Bactericidal action of bismuth in E. coli is also inhibited by BSS.%# Ultrastructural studies
show binding of bismuth complexes to the bacterial wall
E Complexes in – bacterial wall
and periplasmic space (between the inner and outer
– periplasmic space
E Inhibits – urease membrane) of H. pylori with eventual ballooning and
– catalase disintegration of the organism (Figure 4).
– lipase}phospholipase Bismuth salts are effective in suppressing and eradi-
E Inhibits ATP synthesis cating H. pylori as monotherapy.%$–%) Eradication rates
E Inhibits H. pylori adherence ranging from 0 to 32 % have been observed with these
agents.%%, %', %), %* Studies comparing bismuth mono-
Synergism is observed in vitro between CBS and other therapies, however, are not available from the previous
antibiotics, particularly the B lactams.$% RBC also exhibits literature observing clearance and eradication of the
synergism with antibiotics, particularly clarithromycin.$& organism. CBS appears superior to other agents (Table
Clarithromycin resistant strains of H. pylori are sus- 5). A combination of bismuth compounds with other
ceptible in vitro when clarithromycin is combined with antibiotics including tetracycline, nitroimidazoles,
RBC.$' amoxycillin, and clarithromycin results in enhanced
The mechanism of action of bismuth to cause bac- eradication of the organism.%)–&" The mechanisms of
tericidal damage to H. pylori is unclear. Drugs may have impaired activity of antimicrobial combinations in
anti-bacterial action owing to a number of mechanisms humans relates particularly to antibiotic resistance,
including inhibition of cell wall synthesis, inhibition of either primary or acquired, of the H. pylori as well as
cell membrane function, inhibition of protein synthesis, patient compliance to therapy. Primary or acquired
and inhibition of ATP synthesis. Bismuth appears to resistance of H. pylori to bismuth salts has never been
exert its bactericidal action by a number of mechanisms reported.' Bismuth salts have been suggested to decrease
as summarized in Table 4. Complexes of bismuth with the the development of H. pylori resistance to nitro-

A B

Figure 4. (a) H. pylori 120 min after oral administration of bismuth with bacterial wall detachment and structural degradation with
vacuolization, (b) structural degradation with deposition of particulate bismuth complexes in and on the surface of H. pylori.

# 1997 Blackwell Science Ltd, Aliment Pharmacol Ther 11 (Suppl. 1), 27–33
 A C T I O N O F B I S M U T H I N T R E A T M E N T O F H. P Y L O R I I N F E C T I O N 31

Table 5. Clearance and eradication of

Duration
H. pylori with bismuth monotherapy
Dose}day of therapy Clearance Eradication
Substance (mg) (weeks) (%) (%) Reference

BSS 3¬270 4 66 0 43,44

CBS 4¬120 4 59 20 45,46
Bismuth aluminate 3¬300 3 57 – 47
RBC 2¬800 4 – 2 48

imidazoles.&# In vitro studies have shown that RBC
enhances the anti-Helicobacter activity of clarithromycin
when clarithromycin resistant strains are tested.$'
GASTRODUODENAL EFFECTS OF BISMUTH SALTS
effective in healing both duodenal and gastric ulcers, as
well as in experimental ulcer models.%), '" Protection
against non-steroidal anti-inflammatory drugs (NSAIDS),
aspirin and alcohol induced–damage is also noted with
these agents.$$, &&, '#

Bismuth salts have both in vitro and in vivo activity CONCLUSION

against H. pylori as well as other enteropathogenic
bacteria. In addition, these salts exert other effects at
various sites within the gastric and duodenal mucosa.
These effects differ with the different bismuth compounds
and cytoprotective effects have been particularly noted
with BSS,&$ CBS&% and more recently RBC.$$, && The in vitro
and mucosal effects of these three bismuth compounds
are summarized in Table 6. CBS, BSS and RBC exert
cytoprotective with protection against acute gastric
lesions in rats when exposed to stressful agents.&%–&' This
effect is probably mediated by prostaglandins, epithelial
growth factor (EGF) and mucosal bicarbonate
secretion.&$, &(–&* These agents inhibit the action of pepsin
in gastric juice.$$, &) Both CBS and RBC are capable of
protecting gastric mucous from peptic luminal degra-
dation as well as enhancing the properties of mucous.$$, &)
In humans and animal models bismuth salts are
Table 6. Postulated modes of action of CBS, BSS and RBC
Result for indicated
compound*
Action CBS BSS
Protection of gastric mucosa ­ ­
Antibacterial activity ­ ­
Binding to ulcer base and mucus ­ ­
Binding of bile acids ­ ­
Reduction of pepsin output and activity ­ ?
Improvement of mucosal ultrastructure ­ ?
Endogenous prostaglandin and HCO # $
$ Scand J Gastroenterol 1982 ; 17 (Suppl. 80) : 11–16.
secretion
Binding of epidermal growth factor ­ ?
* ­ ¯ effective ; ? ¯ unknown ; # ¯ increase ; $ ¯ decrease.
Bismuth salts have been used for many centuries and
have diverse properties in the upper gastrointestinal
tract. Bismuth compounds including CBS and RBC have
in vitro and in vivo activity against H. pylori. In addition,
the use of these agents may prevent the development of
acquired resistance of Helicobacter to antibiotics. Due
to the advantage of acid suppression as well as
high compliance and low side-effects RBC may offer
advantages over other currently used bismuth salts.
The bismuth salts in current use are safe, have few side-
effects with no documented toxicity when used as
recommended by the manufacturers. Current use of
these compounds in the treatment of gastric and duo-
denal ulcer disease, and H. pylori infection is recom-
mended. The role in treatment of non-ulcer dyspepsia
and NSAID-induced damage is unclear. A greater under-
standing of the local pharmacology of these compounds,
as well as their specific mechanisms of action on H. pylori
is required.
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