Antiulcer Drugs

 An Ulcer is localized erosion in stomach or duodenum. Causes of ulcers are Non-

Steriodal Anti-Inflammatory Drugs (NSAIDS) and Helicobacter pylori infection.
Classification:
1. Antacids :
(a) Na- bicarbonate based they neutralize stomach acid
(b) Ca- carbonate use in rebound acid increase
(c) Mg hydroxide eg (Milk of Magnesia)
(d) Aluminum hydroxide
2. Histamine 2 (H2) antagonists
a. Imidazole ring containing eg cimetidine

b. Furan ring containing eg. Rantidine

c. Thiazole ring containing eg. Famotidine

3. Proton Pump Inhibitors (Benzimidazole derivatives)

a. omeprazole

b. lansoprazole

c. esomeprazole
d. rabeprazole

e pantoprazole
 4. Miscellaneous
a. Sucralfate; it forms polymers in acidic peptic ulcer disease (PUD)
b. Bismuth subsalicylate; it coats esophagus & acts as PUD, GERD
c. Misoprostrol secrete gastric mucous barrier and prevent NSAID-induced peptic ulcers

MODE OF ACTION AND SAR

Histamine 2 (H2) antagonists:
Gastric acid is secreted from parietal cells located mainly in the upper portion of the
stomach and is stimulated by three endogenous substances: gastrin, acetylcholine and
histamine. It is thought that gastrin and acetylcholine act on mat cells to release
histamine: the histamine then acts on the H2-receptors on parietal cells to stimulate acid
secretion. The H2-blockers inhibit gastric acid secretion elicited by histamine or other
H2-agonists in a dose-dependent competitive manner.

Uses: I. Treatment of gastric and duodenal ulcer. 2. The management of hypersecretory

conditions, such as Zollinger—Ellison syndrome, systemic mastocytosis and multiple
endocrine adenomas. 3. Gastroesophageal reflux diseases.
SAR: The H2 receptor antagonists were the result of the intentional modification of the
histamine structure and deliberate search for a chemically related substance that would
act as competitive inhibitor of the H2, receptors. Most of the clinically useful H2
antagonists can be represented by a general structure which is shown below:
 Basic heterocycle group----Flexible chain or aromatic ring--- Polar group system

H2 receptor antagonist must bind but not activate H2 receptor site

1) Addition of aromatic ring: Basic heterocycle group as imidazole
2) Addition of non-polar, hydrophobic substituents like Flexible chain or aromatic ring
3) Addition of a functional group to bind with another binding region and prevent the
conformational change like polar group system.

Above structure of Na –Guanylhistamine shows first antagonist property.

4) The imidazole ring of histamine is not required for competitive antagonism of
histamine at H2-receptors. Other heterocyclic rings (furan, thiophene, thiazole, etc.) may
be used.
5) Separation of the ring and the nitrogen group with the equivalent of a four carbon
chain appears to be necessary for optimum antagonist activity. The isosteric thioether link
is acceptable.
6) The terminal nitrogen group should be polar, non-basic substituents for maximal
antagonist activity. In general, antagonist activity varies inversely with the hydrophilic
character of the nitrogen group.

Synthesis:

PROTON PUMP INHIBITORS

Proton pump inhibitors represent newer class of drugs likely useful for the control of
gastric acidity and the treatment of peptic ulcer. Proton pump inhibitors are used to
heal stomach and duodenal ulcers. This includes stomach ulcers caused by taking non-
steroidal anti-inflammatory drugs. They are also used to relieve symptoms of
oesophagitis (inflammation of the oesophagus) and severe gastro-oesophagcal reflux. a
condition where acid leaks up from the stomach.
MECHANISM OF ACTION
The ultimate mediator of acid secretion is the H + -K + ATPase (proton pump) of the
apical membrane of the parietal cell. Since the pump is unique to parietal cells. Newer
substituted benzimidazoles as specific inhibitors have been developed. These agents
are useful in patients with peptic ulcer.
All the proton pump inhibitors contain a sulphinyl group in a bridge between
substituted benzimidazole and pyridine rings. At neutral pH these agents are chemically
stable, lipid-soluble, weak bases that are devoid of inhibitory activity. These neutral
weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi,
where the drugs become protonarecl and thereby trapped. The protonated agent
rearranges to form a sulphenic acid and a sulphonamide. The sulphonamide interacts
covalently with sulphydryl groups at critical sites in the extracellular domain of the
H + -K + ATPase and inhibits irreversibly and thereby blocks gastric acid secretion.
The activation of omeprazole was illustrated as follows:

SYNTHESIS OF OMPERAZOLE