UNIT I

2.1. GASTRIC PROTON PUMP INHIBITORS

2.1.1. Introduction
Proton Pump Inhibitors (PPIs) are irreversible inhibitors of gastric parietal cell proton pump. This
enzyme promotes the exchange of H + or K + ions, which are required for mediating HCl secretion.
PPIs induce 80-90% inhibition of basal, nocturnal, and food stimulated acid levels after single
administration.

PPIs reduce the acid production by blocking the enzyme present in the stomach wall. Reduction in
the production of acid by stomach prevents the occurrence of ulcers and also facilitates the healing of
ulcers already existing in the oesophagus, stomach, and duodenum.

2.1.2. Classification
Proton pump inhibitors are classified as follows:

Drugs X R1 R2 R3 R4
Omeprazole CH OCH3 CH3 CH3 CH3
Esomeprazole CH OCH3 CH3 CH3 CH3
(S-enantiomer)
Tenatoprazole N OCH3 CH3 CH3 CH3
Lansoprazole CH H CH3 CH2CF3 H
Rabeprazole CH H CH3 (CH2)3OCH3 H
Pantoprazole CH OCHF2 OCH3 CH3 H

2.1.3. Mechanism of Action

The H+-K+-ATPase proton pump of the apical membrane of parietal cell is the mediator of acid
secretion . The newer substituted benzimidazoles have been developed as specific inhibitors
because the H+-K+-ATPase proton pump is unique to parietal cells. These benzimidazoles are used
in peptic ulcer.
The PPIs have a sulphinyl group in a bridge between substituted benzimidazole and pyridine rings.
These agents ar e chemically stable and lipid -soluble weak bases without inhibitory activity at
neutral pH. These neutral weak bases reach the parietal cells from the blood and diffuse into the
secretory canaliculi.

Here the drugs become protonated and trapped. The protonated agent re-arranges for producing
sulphuric acid and sulphonamide, which covalently interacts with sulphhydryl groups of cysteine at
critical sites in the extra cellular domain of the H +- K+-ATPase. Thus, it irreversibly inhibits gastric
acid secretion.

2.1.4. Uses
Proton pump inhibitors are used for treating ulcers and haemorrhagic ulcers caused by Helicobacter
pylori as they inhibit the growth of H. pylori. They also allow the continuous use of NSAIDs in a
patient with known peptic ulcer.

Proton pump inhib itors are also used for preventing recurrent haemorrhagic ulcers. Clot
formation comprises of the processes that weaken in acidic environments, and the clot integrity
is maintained in the ulcer bed by the suppression of gastric acid secretion by proton pump inhibitors.

For example, an intravenous infusion o f omeprazole maintains the intragastric pH above 6, thus, it
supports platelet aggregation and clot stability.

Proton pump inhibitors are superior to H 2-receptor antagonists (like ranitidine) for heali ng gastric
and duodenal ulcers in patients who continue the use of NSAIDs. This is because proton pump
inhibitors can withstand a constant increase in gastric pH.

2.1.5. Study of Individual Drugs

The following gastric PPIs are discussed below:
1) Omeprazole,
2) Lansoprazole,
3) Rabeprazole, and
4) Pantoprazole.

2.1.5.1. Omeprazole
Omeprazole inhibits the proton pump and decreases the amount of acid produced in the stomach.
Mechanism of Action
Omeprazole suppresses gastric acid secretion by inhibiting the H +-K+-ATPase in the gastric parietal
cell. Thus, by acting specifically on the proton pump it blocks the final step in acid production, and
reduces gastric acidity.

Uses
1) It is used for treating GERD and other conditions caused by excessive production of stomach
acid.
2) It is used to promote the healing of erosive oesophagitis (damage caused to oesophagus by the
stomach acid).
3) It is used to relieve heartburn, difficulty in swallowing, and persistent cough.
4) It is used to prevent oesophageal cancer.
5) It is used along with antibiotics to treat gastric ulcer caused by H. pylori.

2.1.5.2. Lansoprazole
Lansoprazole i s a substituted benzimidazole prodrug having the selective and irreversible proton
pump inhibitor activity. It prevents the production of acid in the stomach.

Mechanism of Action
Lansoprazole is an anti -secretory compound. It is a substituted benzimidazole that is devoid of
anticholinergic or H2-receptor antagonist properties. However, it suppresses gastric acid secretion by
inhibiting the H+-K+-ATPase enzyme system at the secretory surface of gastric parietal cell.

Since this enzyme system is the acid (proton) pump in the parietal cell, lansoprazole is considered the
gastric acid-pump inhibitor which inhibits the final step of acid production . This effect is dose -
dependent and inhibits the basal as well as stimulated gastric acid secretion irrespective of the
stimulus.

Uses
1) It is used for treating acid-reflux disorders (like GERD) and peptic ulcer disease.
2) It is used for H. pylori eradication.
3) It is used in combination with NSAIDs for preventing gastrointestinal bleeding.

2.1.5.3. Rabeprazole
 Rabeprazole is an antiulcer drug that blocks the H+-K+-ATPase of the coating gastric cells. It also
inhibits the dose-dependent oppresses basal and stimulated gastric acid secretion.

Mechanism of Action
Rabeprazole is an anti -secretory compound. It is a substituted benzimidazole proton-pump inhibitor
that suppresses gastric acid secretion by inhibiting the H +- K+-ATPase enzyme system at the secretory
surface of gastric parietal cell. Since this enzyme system is the acid (proton) pump i n the parietal
cell, rabeprazole is considered the gastric acid -pump inhibitor which inhibits the final step of acid
production.

Uses
1) It is used in the treatment of Gastroes ophageal reflux disease (GERD) and poorly responsive
systemic GERD.
2) It is used in severe erosive esophagitis.
3) It is used in pathologic hypersecretory conditions, like Zollinger-Ellison syndrome, systemic
mastocytosis, and multiple endocrine adenomas.
4) It is used for treating duodenal ulcers with or without anti-infectives for
Helicobacter pylori.

5) It is also used for curing the daytime or night time heartburn.

2.1.5.4. Pantoprazole
Pantoprazole is a first generation PPI. It is also used for treating other disorders wherein gastric acid
secretion needs to be reduced . Pantoprazole is available in many forms , such as a delayed -
release oral capsule, oral suspension, and intravenous injection.

Mechanism of Action
Pantoprazole is a substituted benzimidazole derivative and a weak base.It collects in the acidic space of the parietal
cell and then converts into active