In conclusion, the present study found that esomeprazole 40 mg daily may be more effective than either omeprazole 20 mg daily, pantoprazole 40 mg daily or lansoprazole 30 mg daily for the rapid relief of heartburn symptoms in patients with endoscopically proven reflux esophagitis.

1. Comparative Study of
Omeprazole and
Esomeprazole
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2. OMEPRAZOLE
• First proton pump inhibitor (PPI) to
reach the market (Losec 1988)
• Used in the treatment and
management of: Peptic ulcer,
Gastroesophageal reflux disease
(GERD); heartburn
• It is the racemic mixture of 50% S-
(–)-Omeprazole and 50% R-(+)-
Omeprazole.
• Popular drug due to long duration
of action and very few side effects

3. • Makers of omeprazole were trying to
find a drug with better bioavailability
• Substitution was varied on both the
pyridine and benzimidazole rings
• Best compound was eventually found to
be the S-enantiomer of omeprazole-
esomeprazole
• Studies show that-
Esomeprazole has longer duration
of action than omeprazole,
Esomeprazole prove to be the drug
of choice for management of
GERD.
ESOMEPRAZOLE

4. OMEPRAZOLE VS
ESOMEPRAZOLE
Points of Discussion:
1. THE PROTON PUMP AND MECHANISM OF INHIBITION
2. METABOLISM OF OMEPRAZOLE AND ESOMEPRAZOLE
3. STEREOCHEMISTRY OF OMEPRAZOLE AND ESOMEPRAZOLE
4. PHARMACOLOGICAL RESPONSE

5. THE PROTON PUMP
• Gastric acid secretion occurs from the gastric parietal cells
• Parietal cells contain receptors for acetylcholine, histamine
and gastrin which ↑HCl through 2nd messenger interactions
Upon binding with their respective ligands.
• In 1976 the proton pump was discovered which contributed to
H+ (protons) in the formation of gastric HCl.
• It was postulated that activation of the proton pump through
acetylcholine, histamine and gastrin led to increased acid
secretion

6. THE PROTON PUMP
• The proton pump is an ATP-dependent hydrogen–potassium
exchanger (H+,K+-ATPase)
• It is an enzyme that is integrated into the membrane of the gastric
parietal cell
• Quaternary protein structure made of one α-subunit and one β-
subunit.
• α subunit, contains active binding site for ATP
• This site is the target binding site for PPIs
• β-subunit is involved in correct membrane integration and targeting
of the enzyme complex to the parietal cell surface
• Upon binding of ATP, the proton pump undergoes conformational
changes (known as E1 and E2 states)
• This change allows exchange of one proton from the parietal cell
into the gastric lumen, for every K+ .

7. THE PROTON PUMP
Factors influencing the stimulation of
gastric acid secretion. An introduction to
medicinal chemistry. Oxford university
press, 2013.
Abe, K., Tani, K., Nishizawa, T. & Fujiyoshi, Y . Electron
density map showing the subunits and binding sites in
the H+,K+-ATPase. Inter‐subunit interaction of gastric
H+, K+‐ATPase prevents reverse reaction of the
transport cycle. The EMBO journal 28, 1637-1643
(2009)

8. MECHANISM OF INHIBITON
PPI carried through blood to the gastric parietal cells
↓
PPIs are weak bases and prodrugs
↓
Activation occurs via protonation at high acidic environment of the gastric lumen
↓
Leads to the formation of a tetracyclic sulphenamide structure
↓
Sulfur atom of the PPI binds to sulfhydryl group of a cysteine residue located on
the active site of the proton pump α subunit
↓
Forms a sulfur bridge through covalent bonding, causing irreversible inhibition of
the proton pump
↓
ATP can not bind to the active site, preventing release of H+ into gastric lumen

9. MECHANISM OF INHIBITON
From Mechanism of inhibition by proton pump inhibitors. An introduction to medicinal chemistry. Oxford university
press, 2013.
1
2
3
4
TETRACYCLIC
STRUCTURE

10. METABOLISM
• Occurs primarily in the liver by cytochrome P450 enzyme family, mostly
by CYP2C19 and CYP3A4 enzymes.
• Reactions: sulfone formation, hydroxylation, and o-demethylation
• Omeprazole is a substrate primarily for CYP2C19
• R-(+)-enantiomer is cleared more rapidly by CYP2C19 mostly through
hydroxylation
• Hydroxylation is much slower in the S-(–)-enantiomer
• It is thought that the hydroxylation is enantioselective
• Combined effect= ↑bioavailability in case of S-(–)-
omeprazole/esomeprazole.
• Recent publications have been reported that this effect is due to the
stereochemistry of the drugs

11. METABOLISM
Barbara Kasprzyk-Hordern.
Metabolites of Omeprazole. Pharmacologically active compounds in the environment and their chirality. Chem. Soc. Rev., 2010,39, 4466-4503

12. STEREOCHEMISTRY
• Asymmetric center not evident at first sight
• Any atom other than carbon can be a chiral center as long as
the molecule exhibits three-dimensional asymmetry
• The molecules may be tetrahedral molecules or even trigonal
pyramidal molecules (where a lone pair is included as one of
the four different groups).
• Sulfur atom that is part of a sulfoxide moiety is an asymmetric
center in esomeprazole as it has a lone pair of electrons and
is tetrahedral.
• Esomeprazole (S-omeprazole) is optically active i.e., it can
rotate the plane of polarized light by a substantial amount
• Omeprazole (racemic mixture) is optically inactive.

13. STEREOCHEMISTRY
A
B
C
A- Non-carbon atoms such as Si, Ge,
N and S atoms can exhibit chirality.
Stereochemistry: Chiral Molecules. in
Organic Chemistry 184-224 (John
Wiley & Sons, 2009)
B- S-(–)-omeprazole
C- R-(+)-omeprazole

14. PHARMACOLOGICAL RESPONSE
• ↑systemic bioavailability of esomeprazole offers the
prospect of improved clinical efficacy and more
effective management of acid-related diseases.
• Study was performed in 36 patients with acid reflux
disease
• Comparisons were performed between the
recommended dosage of omeprazole (20 mg once
daily) and the corresponding dosage of esomeprazole
plus esomeprazole 40mg vs omeprazole 20mg
• Measurements taken: gastric pH level over 24-h
period, plasma concentration of the drugs

15. PHARMACOLOGICAL RESPONSE
Results:
• Percentage of the 24-h
period for which pH
remained > 4 was
significantly higher for
esomeprazole compared
with omeprazole (pH>4 is
essential for healing of
GERD)
• Esomeprazole 40 mg was
significantly more effective
than the 20 mg dosage in
terms of the effective
response
Intra-gastric pH data expressed as the
proportion of patients in whom gastric pH was
above 4 for different durations of the 24-h cycle
(Day 5 of dosing). The gain in acid control with
esomeprazole, 40 mg once daily, for the entire
patient group is well illustrated by this analysis
method.

16. PHARMACOLOGICAL RESPONSE
• Plasma conc. when dosing
with esomeprazole 20 mg
was approximately 80%
higher than with
omeprazole 20 mg
• For esomeprazole 40 mg,
plasma concentration was
over five times higher vs.
omeprazole.
Mean plasma concentration-time profiles
after 5 days' dosing with esomeprazole
(40 and 20 mg once daily) and
omeprazole (20 mg once daily) in 36
patients with symptoms of gastro-
esophageal reflux disease.

17. CONCLUSIONS
• Maintenance of an gastric pH above 4 for the greater part of each 24-
h period is crucial for ensuring esophageal healing and symptom
relief in GERD
• Using this pH threshold, the study revealed that esomeprazole
achieves significantly greater acid control than omeprazole over 24-h
period
• Even though mechanism of action of both esomeprazole and
omeprazole is same, stereo selective metabolism of the S-
enantiomer is less favored  ↑[esomeprazole] in blood
• ↑[esomeprazole] lead to increased delivery of the drug to the lumen
of the parietal cell and hence ↑inhibition of acid secretion
• Esomeprazole proves to be a better choice for the management of
GERD and related diseases