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Patients
at
high risk of
developing gastro-intestinal
complications with a NSAID include those aged over
65 years, those with a history of peptic ulcer disease or
serious
gastro-intestinal
complication,
those
taking
other medicines that
increase the risk of
gastro-intes-
tinal side-effects,
or those with serious co-morbidity.
In
those at risk of ulceration, a proton pump inhibitor can
be considered for protection against
gastric and duo-
denal
ulcers associated with non-selective NSAIDs;
a
H
2
-receptor antagonist such as ranitidine given at twice
the usual dose or misoprostol are alternatives. Colic and
diarrhoea may limit the dose of misoprostol.
A combi-
nation of a cyclo-oxygenase-2 selective inhibitor with a
proton pump inhibitor
may be more appropriate for
those with a history of upper gastro-intestinal
bleeding
or 3 or more risk factors for gastro-intestinal ulceration,
but see NSAIDs and Cardiovascular Events,
p.
631.
NSAID use and
H. pylori
infection are independent risk
factors for gastro-intestinal
bleeding and ulceration.
In
patients already taking a NSAID, eradication of
H. pylori
is unlikely to reduce the risk of NSAID-induced bleeding
or ulceration.
However,
in patients with dyspepsia or a
history of gastric or duodenal
ulcer,
who are
H.
pylori
positive, and who are about to start long-term treatment
with a non-selective NSAID,
eradication of
H.
pylori
may reduce the overall risk of ulceration.
If the
NSAID can be discontinued
in a patient who has
developed an ulcer,
a proton pump inhibitor
usually
produces
the
most
rapid healing;
alternatively,
the
ulcer can be treated with a H
2
-receptor antagonist
or
misoprostol.
If
treatment with a non-selective NSAID needs to con-
tinue
,
the following options are suitable:
.
Treat
ulcer with a proton pump inhibitor and on
healing continue the proton pump inhibitor (dose
not normally reduced because asymptomatic ulcer
recurrence may occur);
.
Treat
ulcer with a proton pump inhibitor and on
healing switch to misoprostol for maintenance ther-
apy (colic and diarrhoea may limit
the dose of
misoprostol);
.
Treat ulcer with a proton pump inhibitor and switch
non-selective NSAID to a cyclo-oxygenase-2 selec-
tive inhibitor,
but see NSAIDs and Cardiovascular
Events,
p.
631;
on healing,
continuation of the pro-
ton pump inhibitor
in patients with a history of
upper
gastro-intestinal
bleeding
may
provide
further protection against recurrence.
If
treatment with a cyclo-oxygenase-2 selective inhibitor
needs
to continue
,
treat
ulcer
with a proton pump
inhibitor;
on healing continuation of
the proton pump
inhibitor
in patients
with a history of
upper
gastro-
intestinal
bleeding
may
provide
further
protection
against recurrence.
1.3.1
H
2
-receptor antagonists
Histamine H
2
-receptor antagonists heal
gastric and
duodenal
ulcers
by reducing gastric acid output
as a
result of histamine H
2
-receptor blockade;
they are also
used to relieve symptoms of
gastro-oesophageal reflux
disease
(section 1.1). H
2
-receptor antagonists should not
normally
be
used
for
Zollinger-Ellison
syndrome
because
proton pump inhibitors
(section 1.3.5)
are
more effective.
Maintenance treatment with low doses for the preven-
tion of peptic ulcer disease has largely been replaced in
Helicobacter
pylori
positive patients
by eradication
regimens (section 1.3).
H
2
-receptor antagonists are used for the treatment
of
functional dyspepsia
(section 1.1).
H
2
-receptor antago-
nists may be used for the treatment of
uninvestigated
dyspepsia
in patients without alarm features.
H
2
-receptor antagonist therapy can promote healing of
NSAID-associated ulcers
(particularly duodenal)
(sec-
tion 1.3).
Treatment with a H
2
-receptor antagonist has not been
shown to be beneficial
in haematemesis and melaena,
but prophylactic use reduces the frequency of bleeding
from
gastroduodenal
erosions
in hepatic coma
,
and
possibly in other
conditions requiring intensive care.
H
2
-receptor
antagonists also reduce the risk of
acid
aspiration
in obstetric patients at delivery (Mendelson’s
syndrome).
Cautions
H
2
-receptor antagonists might mask symp-
toms of
gastric cancer;
particular
care is required in
patients presenting with ‘alarm features’
(see p.
43),
in
such cases
gastric malignancy should be ruled out
before treatment.
Side-effects
Side-effects of
the H
2
-receptor antago-
nists include diarrhoea,
headache,
and dizziness.
Rash
(including erythema multiforme and toxic epidermal
necrolysis)
occurs
less
frequently.
Other
side-effects
reported rarely or very rarely include hepatitis,
chole-
static
jaundice,
bradycardia,
psychiatric
reactions
(including confusion,
depression,
and hallucinations)
particularly in the elderly or the very ill, blood disorders
(including leucopenia, thrombocytopenia, and pancyto-
penia),
arthralgia,
and myalgia.
Gynaecomastia and
impotence
occur
occasionally
with
cimetidine
and
there are isolated reports with the other
H
2
-receptor
antagonists.
Interactions
Cimetidine retards
oxidative hepatic
drug metabolism by binding to microsomal cytochrome
P450.
It
should be avoided in patients stabilised on
warfarin,
phenytoin,
and theophylline (or
aminophyl-
line),
but other interactions (see Appendix 1) may be
of
less clinical
relevance.
Famotidine,
nizatidine,
and
ranitidine do not share the drug metabolism inhibitory
properties of cimetidine.
CIMETIDINE
Indications
benign gastric and duodenal ulceration,
stomal ulcer,
reflux oesophagitis,
other conditions
where gastric acid reduction is beneficial (see notes
above and section 1.9.4)
Cautions
see notes above; interactions: Appendix 1
(histamine H
2
-antagonists) and notes above
Hepatic impairment
increased risk of confusion;
reduce dose
Renal impairment
reduce dose; 200 mg 4 times daily
if eGFR 30–50 mL/minute/1.73 m
2
;
200 mg 3 times
daily if eGFR 15–30 mL/minute/1.73 m
2
;
200 mg
twice daily if eGFR less than 15 mL/minute/1.73 m
2
;
occasional risk of confusion
Pregnancy
manufacturer advises avoid unless essen-
tial
Breast-feeding
significant amount present in milk—
not known to be harmful but manufacturer advises
avoid
BNF 61
1.3.1 H
2
-receptor antagonists
51
1
Gastro-intestinal system