This document discusses proton pump inhibitors, which are a class of drugs used to treat gastric ulcers. It begins by classifying antiulcer agents and listing examples of proton pump inhibitors like omeprazole and pantoprazole. It then describes the key structural features of proton pump inhibitors that allow them to inhibit acid secretion. The document explains the mechanism of action of proton pump inhibitors, how they form a sulfenamide intermediate that binds irreversibly to cysteine residues on the hydrogen-potassium ATPase pump. It also discusses the pharmacokinetic properties and metabolic pathways of proton pump inhibitors.

1. ANTIULCER AGENTS:-
PROTON PUMP INHIBITORS
Dr. Vishal S. More,
Assistant Professor,
Dept. of Pharmaceutical Chemistry,
Amrutvahini College of Pharmacy, Sangamner.

2. CLASSIFICATION
I. Drugs for Reduction of gastric acid secretion.
a. H2-antihistamines: Cimetidine, Ranitidine, Famotidine.
b. Proton pump inhibitors: Omeprazole, Lansoprazole,
Tenatoprazole, Rabeprazole, Pantoprazole.
c. Anticholinergics: Pirenzepine, Propantheline, Oxyphenonium.
d. Prostaglandin analogues: Misoprostol.
II. Drugs for Neutralization of gastric acid (Antacids).
a. Systemic: NaHCO3, Sodium citrate.
b. Non systemic: Mg(OH)2, CaCO3, Aluminium hydroxide gel,
Magnesium trisilicate.
III. Ulcer protectives:-
Sucralfate, Colloidal Bismuth subcitrate (CBS).
IV. Anti-Helicobacter pylori drugs:-
Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline.

3. BENZIMIDAZOLE PROTON PUMP INHIBITORS
Substituted
pyridine ring
Substituted
benzimidazole
Methylsulfinyl linking group

4. BENZIMIDAZOLE PROTON PUMP INHIBITORS

5. BENZIMIDAZOLE PROTON PUMP INHIBITORS

6. The three main structural features of omeprazole (i.e.,
the substituted pyridine ring; the substituted
benzimidazole; and the methylsulfinyl linking
group, by which these two ring systems are attached
to one another) are essential, either in generating the
active form from its inactive precursor or in binding
irreversibly with the H+/K+-ATPase enzyme. For this
reason, compounds inhibiting acid secretion by this
mechanism and lacking one or more of these features
are scarce.
SAR of Proton Pump Inhibitors
Substituted
pyridine ring
Substituted
benzimidazole
Methylsulfinyl
linking group
5
3
2
7
6
1
4
1
2
3
4
5
6

7. SAR NOTES (OMEPRAZOLE)
The methoxy group at position 4 of the pyridine ring
donates electrons through resonance to the pyridine
nitrogen. This not only increases the percentage of
cationic pyridine (which sequesters the drug at the site
of action), it also increases the nucleophilic character
of any molecules of the PPI with an unionized pyridine
nitrogen. This in turn facilitates the intramolecular
nucleophilic attack at C2 of the benzimidazole active
sulfenamide ring, leading to the formation of the and
sulfenic acid forms.
The methyl groups at positions 3 and 5 also enhance
the nucleophilic character of the unionized pyridine
nitrogen through positive induction, a sigma bond
effect.

8. SAR NOTES (OMEPRAZOLE)
The C2 position of the benzimidazole is made more
electrophilic by the pi electron donating effect of the
benzimidazole 5-OCH3 group, which enhances N3
protonation that in turn pulls electrons from C2
through sigma bonds. The OCH3 group does exert a
negative inductive effect, but the overall impact on
the benzimidazole N3 is electronic enrichment.
The rate of formation of these active uncharged
(pyridine) and charged (benzimidazole) forms is
directly correlated with the onset of relief from
symptoms. We will see that most of the newer PPIs
on the market (including esomeprazole) have a faster
onset of antisecretory action than omeprazole.

9. Moreover, for irreversible proton-pump inhibitors
to achieve selective biological activity, their
mechanism of action demands that they have
relatively high chemical stability around neutral
pH, but be readily activated at low pH. This
chemical profile also influences attendant issues
such as synthesis, formulation, and storage, and
because biological activity of this class of
compounds often correlates with chemical
liability, not all compounds, which achieve potent
inhibitory behaviour in vitro, are viable drug
candidates because they are inherently too
chemically unstable.

10. The gastric proton-pump inhibitors currently
available all retain the same key chemical
features present in omeprazole, indicating that
the structural requirements to achieve irreversible
inhibition of the gastric ATPase enzyme are
precisely defined.
The potency of irreversible proton-pump
inhibitors is a time-and pH-dependent property,
making comparison of their in vitro potency
difficult, given the wide range of assay conditions
employed.

11. FACTORS INFLUENCING THE RELEASE OF GASTRIC ACID

12. ROLE OF THE PROTON PUMP IN SECRETING HYDROCHLORIC ACID

13. MOA OF PROTON PUMP INHIBITORS

14. Parietal cells contain an H, K-ATPase or hydrogen ion pump that
secretes proton (H) in exchange for the uptake of K ion. Secretion of
acid by gastric parietal cells is stimulated by various mediators at
receptors located on the basolateral membrane, including histamine
agonism of H2-receptors (cellular), gastrin activity at G receptors
(blood), and acetylcholine (ACh) at M3 muscarinic receptors
(neuronal). Gastric and muscarinic receptors modulate acid
secretion through calcium-dependent processes, while the
H2-receptor is coupled to adenylate cyclase.
The adenylate cyclase pathway, and therefore acid secretion, is
inhibited by intracellular prostaglandins of the E series. These
prostaglandins also stimulate other GI epithelial cells to secrete
mucous and bicarbonate, and enhance blood flow through gastric
tissues. All of these prostaglandin-mediated actions have acid
neutralizing and gastric tissue protective properties referred to
generally as “cytoprotection.”
When there is hypersecretion of gastric acid or breakdown of
muscosal cell defenses, including bacterial infection, gastric
tissues and contiguous structures (esophagus, intestines) may
become compromised and ulcerated.
Normal Physiology

15. These drugs suppress gastric acid secretion through
H+ K+ ATPase pump, the two major signalling
pathways that are present with the parietal cells, that
is, cAMP dependent and Ca2+. The respective receptors
for the actions are M3 and H2.
These receptors are modulated through the respective
ionic mechanism and elicited by the acetylcholine from
M3 and histamine from H2 receptor for release of the
gastric acid mediated through H+ K+ ATPase pump.
The proton pump inhibitors act on these receptors
and inhibit H+ K+ ATPase, and reduce the activation
of parietal cells to release the gastric acid.
MOA OF PROTON PUMP INHIBITORS

16. MOA OF PROTON PUMP INHIBITORS
Sunfenamide
intermediate

17. Mechanism
of inhibition
by
Proton
Pump
Inhibitors

18. The benzimidazole PPIs are chemically converted by acid to a
sulfenamide intermediate that inhibits the proton pump via
covalent interaction with sulfhydryl groups with cysteine
residues of the H, K-ATPase pump. All of the PPIs have been
shown to react with cysteine 813 of pump, but some bind to
additional pump sulfhydryl residues as well. For example,
omeprazole and esomeprazole also react with cysteine 892, and
pantoprazole with cysteine 822 and lansoprazole to cysteine
321. Cysteines 321, 813, and 822 are all in the proton-
transport domain of the H, K-ATPase system, whereas cysteine
892 is on the external luminal surface and does not affect
pump transport ability.
The bioaccumulation and activation of the PPIs within the
acidic environment of the parietal cell also ensures specificity of
pharmacologic action. The acid lability of the benzimidazole
PPIs dictates that these drugs must be formulated as delayed-
release, enteric-coated granular dosage forms.

19. PHARMACOKINETIC PROPERTIES OF
PROTON PUMP INHIBITORS

20. PKa VALUES OF BENZIMIDAZOLE
PROTON PUMP INHIBITORS
5
3
2
7
6
1
4
1
2
3
4
5
6

21. Metabolic transformations of PPIs

22. Metabolic transformations of PPIs
Metabolism of omeprazole and other proton pump inhibitors occurs
primarily in the liver. The sulphonated, hydroxylated, and
O-demethylated metabolites have been reported as products. The
oxidative metabolism of omeprazole is catalyzed principally by CYP2C19
(primarily 5’-hydroxylation and to a lesser extent, benzimidazole O
demethylation). Different proton pump inhibitors depend differently on
CYP2C19 for the oxidative metabolism, and the enantiomer show
variation of independence on CYP2C19 and other pathways.
Pantaprazole and lansoprazole show greater metabolism via CYP2C19.
The enantiomer being affected differently than Rabeprazole, which is
metabolized only to a small extent by oxidative CYP450 enzyme.

23. FDA Indicators for
Anti-hypersecretory agents

24. https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC1637016/
FOR MORE INFORMATION FOLLOW THE
BELOW LINK

25. Thank you