Clinical Pharmacology and Therapeutics

PEPTIC ULCERATION 251
Ranitidine has a similar profile of minor side effects to cimetidine.
There have been some very rare reports of breast
swelling and tenderness in men. However, unlike cimetidine,
ranitidine does not bind to androgen receptors, and impotence
and gynaecomastia in patients on high doses of cimetidine
have been reported to resolve when they were switched
to ranitidine. Cardiovascular effects have been even more
infrequently reported than with cimetidine. Small amounts of
ranitidine penetrate the central nervous system (CNS) and
(like, but less commonly than, cimetidine) it can (rarely) cause
mental confusion, mainly in the elderly and in patients with
hepatic or renal impairment.
Drug interactions
Ranitidine has a lower affinity for cytochrome P450 than
cimetidine and does not inhibit the metabolism of warfarin,
phenytoin and theophylline to a clinically significant degree.
Choice of H 2 -antagonist
All of the H 2 -receptor antagonists currently available in the UK
are effective in peptic ulceration and are well tolerated.
Cimetidine and ranitidine are most commonly prescribed and
have been available for the longest time. Cimetidine is the least
expensive, but in young men who require prolonged treatment
ranitidine may be preferable, due to a lower reported incidence
of impotence and gynaecomastia. Ranitidine is also preferable
in the elderly, where cimetidine occasionally causes
confusion, and also when the patient is on drugs whose metabolism
is inhibited by cimetidine (e.g. warfarin, phenytoin or
theophylline).
Other H 2 -receptor antagonists available for use in the UK
include famotidine and nizatidine, but they offer no significant
advantage over ranitidine.
PROTON-PUMP INHIBITORS
The proton-pump inhibitors inhibit gastric acid by blocking the
H /K -adenosine triphosphatase enzyme system (the proton
pump) of the gastric parietal cell. Examples are omeprazole,
esomeprazole, lansoprazole, pantoprazole and rabeprazole.
The main differences, if any, appear to be in relation to drug
interactions. As yet there do not appear to be any clinically significant
drug interactions with pantoprazole, whereas omeprazole
inhibits cytochrome P450 and lansoprazole is a weak
inducer of cytochrome P450. The indications for proton-pump
inhibitors include the following:
• benign duodenal and gastric ulcers;
• NSAID-associated peptic ulcer and gastro-duodenal
erosions;
• in combination with antibacterial drugs to eradicate
H. pylori;
• Zollinger–Ellison syndrome;
• gastric acid reduction during general anaesthesia;
• gastro-oesophageal reflux disease (GORD);
• stricturing and erosive oesophagitis where they are the
treatment of choice.
DRUGS THAT ENHANCE MUCOSAL RESISTANCE
PROSTAGLADIN ANALOGUES
Misoprostol is a synthetic analogue of prostaglandin E 1 which
inhibits gastric acid secretion, causes vasodilatation in the submucosa
and stimulates the production of protective mucus.
Uses
These include the following:
1. healing of duodenal ulcer and gastric ulcer, including
those induced by NSAIDs;
2. prophylaxis of gastric and duodenal ulceration in patients
on NSAID therapy.
Adverse effects
Diarrhoea, abdominal pain, nausea and vomiting, dyspepsia,
flatulence, abnormal vaginal bleeding, rashes and dizziness
may occur. The most frequent adverse effects are gastrointestinal
and these are usually dose dependent.
Contraindications
Pregnancy (or desired pregnancy) is an absolute contraindication
to the use of misoprostol, as the latter causes abortion.
BISMUTH CHELATE
Colloidal tripotassium dicitratobismuthate precipitates at acid
pH to form a layer over the mucosal surface and ulcer base,
where it combines with the proteins of the ulcer exudate. This
coat is protective against acid and pepsin digestion. It also
stimulates mucus production and may chelate with pepsin,
thus speeding ulcer healing. Several studies have shown it to
be as active as cimetidine in the healing of duodenal and gastric
ulcers after four to eight weeks of treatment. It has a direct
toxic effect on H. pylori and may be used as part of triple
therapy.
Bismuth chelate elixir is given diluted with water 30 minutes
before meals and two hours after the last meal of the day.
This liquid has an ammoniacal, metallic taste and odour
which is unacceptable to some patients, and chewable tablets
can be used instead. Antacids or milk should not be taken concurrently.
Ranitidine bismuth citrate tablets are also available for the
treatment of peptic ulcers and for use in H. pylori eradication
regimes.
Adverse effects
Adverse effects include blackening of the tongue, teeth and
stools (causing potential confusion with melaena) and nausea.
The latter may limit dosing. Bismuth is potentially neurotoxic.
Urine bismuth levels rise with increasing oral dosage, indicating
some intestinal absorption. Although with normal doses the
blood concentration remains well below the toxic threshold,
bismuth should not be used in renal failure or for maintenance
treatment.