here is the presentation shows functioning of proton pump and drugs acting on proton pump as PPI inhibitors.

1. FUNCTIONINGOF PROTON PUMP
INHIBITORS (PPI)
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Dr. Akhil Nagar
RC Patel Institute of Pharmaceutical
Education and Research

2. Proton Pump Inhibitors
 Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium
adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly
just gastric proton pump) of the gastric parietal cell. The proton pump is the
terminal stage in gastric acid secretion, being directly responsible for secreting
H+ ions into the gastric lumen, making it an ideal target for inhibiting acid
secretion. (“Irreversibility” refers to the effect on a single copy of the enzyme; the
effect on the overall human digestive system is reversible, as the enzymes are
naturally destroyed and replaced with new copies.)
 Targeting the terminal-step in acid production, as well as the irreversible nature of
the inhibition, result in a class of drugs that are significantly more effective than
H2 antagonists and reduce gastric acid secretion by up to 99%.
Department of Pharmaceutical Chemistry 2

3.  The lack of the acid in the stomach will aid in the healing of
duodenal ulcers, and reduces the pain from indigestion and
heartburn, which can be exacerbated by stomach acid. However, lack
of stomach acid is also called hypochlorhydria, the lack of sufficient
hydrochloric acid, or HCl.
 The proton pump inhibitors are given in an inactive form. The
inactive form is neutrally charged (lipophilic) and readily crosses
cell membranes into intracellular compartments (like the parietal cell
canaliculus) that have acidic environments. In an acid environment,
the inactive drug is protonated and rearranges into its active form. As
described above, the active form will covalently and irreversibly
bind to the gastric proton pump, deactivating it.
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4. Development
 In the late 60s Astra produced very effective drug in the rat but was completely
ineffective in humans and project was dropped
 Restarted in 1972 using dog model
 Another pharmaceutical company reported an antisecretory compound (CMN 131)
 The second company dropped the project because the compound showed severe acute
toxicity
 It was assumed the toxicity was due to the presence of the thioamide which was
eliminate by incorporating it into or in between heterocyclic ring systems.
 Incorporation of substituent on benzimidazole eliminated thyroid enlargement effect
patented by a
Hungarian company
for the use inTB
more potent
but enlarge
thyroid gland
inflammation and
necrosis in blood
vessels
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5. In 1977 the proton pump was discovered
to be the final step in acid secretion.
In the early 80s it was shown that the
substituted benzimidazoles blocked the
proton pump
Since weak bases accumulate in the acidic compartment, substituents were added to the
pyridine ring to obtain a pKa that maximized the accumulation in the parietal cell
 The resulting compound was called Omeprazole Lifelong toxicological studies at very
high doses in rats revealed the development of endocrine tumors in the stomach
 This halted clinical studies until it was shown the tumors were the result of the very
high doses causing severe suppression
 Restarted, but resulted in extreme caution in the recommended dose, 20 mg
 Omeprazole was originally marketed as Losec but renamed Prilosec to avoid confusion
with Lasix 5

6. Mechanism
 Inhibiting the gastric H+/K+–ATPase located in the secretory membranes of
the parietal cells, responsible for gastric acid production
 Omeprazole is a prodrug and is transformed within the acidic canaliculi of
the parietal cells into the active form, a sulfenamide
 This sulfenamide reacts with thiol groups in the enzyme, forming a
disulfide link which inactivates the enzyme. The high specificity of action
is due to several factors.
1. Omeprazole is a weak base (pKa 4.0), therefore concentrates in acidic
canaliculi of the parietal cells
2. The low pH causes the conversion into the active species close to the
target enzyme
3. The active species is a permanent cation which can not escape the
canaliculi
4. At the higher pHs found in the body, Omeprazole has good stability.
Commercial products are enteric coated to prevent gastric
decomposition
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7. Department of Pharmaceutical Chemistry 7
CH3
O
NH
CH3
O
O
N
SN
Rabeprazole
NH
CH3
O
OF3C
O
N
SN
O
CH3
Pantoprazole
O
O
CH3
N
S
NH
N
CF3
Lansoprazole

8.  The pH at which half of the maximum rate of activation occurs is 3.0 for
Pantoprazole, 4.0 for Omeprazole and 5.0 for Lansoprazole
 Dexlansoprazole was approved in 2008
 All PPIs are rapidly converted at pH less than 2.0, but above 5.0,
Rabeprazole has been shown to have a faster rate of activation and thus
proton pump inhibition
 Differences in structure result in differences in pharmacokinetics, however,
differences in oral bioavailability are not clinically important
 All PPIs have similar potencies
 Undergo first pass metabolism primarily by CYP3A4 and CYP2C19
 All the PPIs are chiral because of the sulfur. Both isomers are converted
into the nonchiral active species at the same rate. In in vivo, the S
omeprazole (esomeprazole) produced higher plasma concentrations
because it undergoes less metabolism by CYP 2C19 and thus produces 70%
higher AUC than Omeprazole.
The pKa and the hydrophobicity of the PPIs determine the extent to which
it accumulates in the canalicular lumen. The rate of enzyme inhibition
corresponds to the rate of sulfenamide formation.
Which one is faster acting?
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9. Please watch the video
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 https://www.youtube.com/watch?time_conti
nue=64&v=_fa60VhclNo
 https://youtu.be/MTOkPl5deHw

10. THANK YOU
Department of Pharmaceutical Chemistry 10