(Redirected from H2-receptor antagonist)
Cimetidine, the prototypical H
2-receptor antagonist.
An 'H
2-receptor antagonist', (H
2RA) often shortened to 'H
2 antagonist', is a
drug used to block the action of
histamine on
parietal cells in the
stomach, decreasing
acid production by these cells. These drugs are used in the treatment of
dyspepsia; however, their use has waned since the advent of the more effective
proton pump inhibitors.
Like the
H1-antihistamines, the H
2 antagonists are
inverse agonists rather than true
receptor antagonists.
History and development
Cimetidine was the prototypical histamine H
2-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now
GlaxoSmithKline) to develop a
histamine receptor antagonist to suppress stomach acid secretion.
In
1964 it was known that
histamine was able to stimulate the secretion of stomach acid, but also that traditional
antihistamines had no effect on acid production. From these facts the SK&F scientists postulated the existence of two histamine receptors. They designated the one acted on by the traditional antihistamines H
1, and the one acted on by histamine to stimulate the secretion of stomach acid H
2.
The SK&F team used a
rational drug design process starting from the structure of histamine - the only design lead, since nothing was known of the then hypothetical H
2 receptor. Hundreds of modified compounds were synthesised in an effort to develop a model of the receptor. The first breakthrough was ''N
α''-guanylhistamine, a partial H
2-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of
burimamide - the first H
2-receptor antagonist. Burimamide, a specific
competitive antagonist at the H
2 receptor 100-times more potent than ''N
α''-guanylhistamine, proved the existence of the H
2 receptor.
Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the
pKa of the compound, lead to the development of
metiamide. Metiamide was an effective agent; however, it was associated with unacceptable
nephrotoxicity and
agranulocytosis. It was proposed that the toxicity arose from the
thiourea group, and similar
guanidine-analogues were investigated until the ultimate discovery of
Cimetidine (common brand name Tagamet).
Ranitidine (common brand name Zantac) was developed by Glaxo (also now
GlaxoSmithKline) in an effort to match the success of Smith, Kline & French with cimetidine. Ranitidine was also the result of a rational drug design process utilising the by-then-fairly-refined model of the histamine H
2 receptor and quantitative structure-activity relationships (
QSAR).
Glaxo refined the model further by replacing the
imidazole-ring of cimetidine with a
furan-ring with a
nitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer
adverse drug reactions), longer-lasting action, and ten times the activity of cimetidine.
Ranitidine was introduced in
1981 and was the world's biggest-selling prescription drug by
1988. The H
2-receptor antagonists have since largely been superseded by the even more effective
proton pump inhibitors, with
omeprazole becoming the biggest-selling drug for many years.
Pharmacology
The H
2 antagonists are competitive inhibitors of
histamine at the
parietal cell H
2 receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. They accomplish this by two mechanisms: histamine released by
ECL cells in the stomach is blocked from binding on parietal cell H
2 receptors which stimulate acid secretion, and other substances that promote acid secretion (such as
gastrin and
acetylcholine) have a reduced effect on parietal cells when the H
2 receptors are blocked.
Clinical use of H2-antagonists
Indications
H
2-antagonists are clinically used in the treatment of acid-related
gastrointestinal conditions. Specifically, these indications may include:
[1]
★
peptic ulcer disease (PUD)
★
gastroesophageal reflux disease (GERD)
★
dyspepsia
★ stress ulcer prophylaxis (raniditine)
People that suffer from heartburn (GERD) infrequently may take either
antacids or H
2-receptor antagonists for treatment. H
2-antagonists offer several advantages over antacids including longer duration of action (6–10 hours vs 1–2 hours for antacids), greater efficacy, and ability to be used prophylactically before meals to reduce the chance of heartburn occurring.
Proton pump inhibitors, however, are the preferred treatment for
erosive oesophagitis since they have been shown to promote healing better than H
2-antagonists.
Some studies also suggest that H
2-antagonists might be effective in treating
herpes viruses, such as
shingles and
herpes simplex [1].
Adverse drug reactions
H
2 antagonists are generally well-tolerated, except for
cimetidine where all of the following
adverse drug reactions (ADRs) are ''common''. Infrequent ADRs include
hypotension. Rare ADRs include:
headache, tiredness, dizziness, confusion,
diarrhoea, constipation, and rash.
[2] Additionally, cimetidine may also cause
gynecomastia in males, loss of libido, and
impotence, which are reversible upon discontinuation.
Drug interactions
With regard to
pharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms of
drug metabolism and elimination through the liver
cytochrome P450 pathway. Specifically, cimetidine is an inhibitor of the P450 enzymes
CYP1A2,
CYP2C9,
CYP2C19,
CYP2D6,
CYP2E1, and
CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their
serum concentrations to
toxic levels. Examples of drugs affected include:
warfarin,
theophylline,
phenytoin,
lidocaine,
quinidine,
propranolol,
labetalol,
metoprolol,
tricyclic antidepressants, some
benzodiazepines, dihydropyridine
calcium channel blockers,
sulfonylureas,
metronidazole, and some recreational drugs such as
ethanol and
MDMA.
Examples
Cimetidine was the prototypical member of the H
2 antagonists. Further developments, using quantitative structure-activity relationships (
QSAR) led to the development of further agents with improved tolerability-profiles. In the United States, all four members of the group are available over the counter in relatively low doses, and have become extremely popular medications marketed to heartburn sufferers.
★
cimetidine (Tagamet)
★
ranitidine (Zantac)
★
famotidine (Pepcid)
★
nizatidine (Axid, Tazac)
References
1. Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3
2.
★ Katzung, Bertram G. (2004). Basic and Clinical Pharmacology, 9th ed. ISBN 0-07-141092-9
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