Proton Pump

Inhibitors

By
Gunjan Kalyani, M. Pharm.
Assistant Professor
Columbia Institute of Pharmacy
Raipur 493111, Chhattisgarh, India
Mobile: +91-8349204583
Mail ID: kalyani.gunjan@yahoo.in

Former Research Fellow

National Center for Natural Resources (NCNR)
Pt. Ravishankar Shukla University, Raipur 492010, India
 Proton Pump Inhibitors
Proton pump inhibitors were introduced in 1980 for the treatment of
heartburn, ulcers and Gastroesophageal reflux disease (GERD).
Omeprazole was the first drug in this class, introduced in 1989. Since then, four
other PPIs viz lansoprazole, rabeprazole, pantoprazole and esomeprazole have
been introduced in 1995, 1999, 2000 and 2001 respectively.

OMEPRAZOLE
Description
Omeprazole (PRILOSEC) is a substituted benzimidazole, 5-methoxy-2-[[(4-
methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1Hbenzimidazole, a
compound that inhibits gastric acid secretion. Its empirical formula is
C17H19N3O3S, with a molecular weight of 345.42.

The Structure

006 - 07 00

Omeprazole is a white to off-white crystalline powder which melts with

decomposition at about 155°C. It is a weak base, freely soluble in ethanol and
methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in
water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid
media, but has acceptable stability under alkaline conditions.

Mechanism of Action
Omeprazole belongs to a new class of antisecretory compounds, the substituted
benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic
properties, but that suppress gastric acid secretion by specific inhibition of the
H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal
cell. Because this enzyme system is regarded as the acid (proton) pump within the
gastric mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect is dose-
related and leads to inhibition of both basal and stimulated acid secretion
irrespective of the stimulus.
 Indications
A. Treatment of gastric ulcer (GU), erosive esophagitis (EE), gastroesophageal reflux
disease (GERD) with or without esophageal lesion.
B. Maintenance therapy of EE.
C. Eradication of Helicobacter pylori in triple therapy with clarithromycin and amoxicillin
or in double therapy with clarithromycin only.

LANSOPRAZOLE

Description
Lansoprazole (PREVACID) is a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-
trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric
acid secretion. Its empirical formula is C16H14F3N3OS with a molecular weight of 369.37.

The Structure

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with

decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide;
soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate,
dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane
and water.
Lansoprazole is stable when exposed to light for up to two months. The compound degrades in
aqueous solution, the rate of degradation increasing with decreasing pH. At 25°C the t½ is
approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0.

Mechanism of action
Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles,
that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but that
suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at
the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as
the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric
acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-
related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective
of the stimulus.
Indications
A. Treatment of duodenal ulcer (DU), both H. pylori positive and negative, active benign GU,
GERD, EE and pathological hypersecretory conditions, including Zollinger-Ellison
syndrome (ZES).
B. Maintenance therapy of DU and EE.
C. Eradication of H. pylori in triple therapy with clarithromycin and amoxicillin, or in double
therapy with amoxicillin only.

PANTOPRAZOLE

Description
Pantoprazole sodium (PROTONIX) is a substituted benzimidazole, sodium 5-
(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl] sulfinyl]-1H-benzimidazole
sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C
16H14F2N3NaO4 S x 1.5 H2O, with a molecular weight of 432.4.

The Structure

Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic.

Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely
soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in
n-hexane.
The stability of the compound in aqueous solution is pH-dependent.
The rate of degradation increases with decreasing pH. At ambient temperature, the degradation
half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8.

Mechanism of Action
Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid
production by forming a covalent bond to two sites of the (H+,K+)-ATPase enzyme system at
the secretory surface of the gastric parietal cell. This effect is dose-related and leads to
inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The
binding to the (H+,K+)-ATPase results in a duration of antisecretory effect that persists longer
than 24 hours.

Indication
Treatment of EE associated with GERD.
The manufacturer of pantoprazole IV is also pursuing the GERD indication for this formulation.
RABEPRAZOLE

Description

Rabeprazole sodium (ACIPHEX) is a substituted benzimidazole that inhibits gastric acid

secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-
2- pyridinyl]-methyl] sulfinyl]-1H–benzimidazole sodium salt. It has an empirical formula of
C18H20N3NaO3S and a molecular weight of 381.43.

The Structure

Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water

and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether
and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly
degraded in acid media, and is more stable under alkaline conditions.

ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets

containing 20 mg of rabeprazole sodium. Inactive ingredients are mannitol, hydroxypropyl
cellulose, magnesium oxide, low-substituted hydroxypropyl cellulose, magnesium stearate,
ethylcellulose, hydroxypropyl methylcellulose phthalate, diacetylated monoglycerides, talc,
titanium dioxide, carnauba wax, and ferric oxide (yellow) as a coloring agent.

Mechanism of Action
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole
proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor
antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+,
K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is
regarded as the acid (proton) pump within the parietal cell, rabeprazole has been
characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of
gastric acid secretion.

Indications
Treatment of erosive or ulcerative GERD, DU and hypersecretory syndromes including
ZES.
Maintenance of erosive or ulcerative GERD.
 ESOMEPRAZOLE

Description

Esomeprazole sodium (NEXIUM) for Injection is (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-

pyridinyl)-methyl]sulfinyl]- 1 H- benzimidazole sodium a compound that inhibits gastric acid
secretion. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the Sand R-
isomers. Its empirical formula is C17H18N3O3SNa with molecular weight of 367.4 g/mol (sodium
salt) and 345.4 g/mol (parent compound).

Esomeprazole sodium is very soluble in water and freely soluble in ethanol (95%).

The Structure

Mechanism of Action
Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific
inhibition ofthe H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole
are protonated and converted in the acidic compartment of the parietal cell forming the active
inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole
blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related
up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

Indications
GERD, healing of EE, maintenance of healing of EE, H. pylori Eradication to reduce the risk of
duodenal ulcer recurrence in triple therapy with clarithromycin and amoxicillin
{mospagebreak title=Pharmacokinetics, dosing, and drug interactions}
PHARMACOKINETICS

Absorption-
Omeprazole and lansoprazole are formulated as enteric-coated granules, whereas rabeprazole
and pantoprazole are enteric- coated tablets. Upon leaving the stomach, the granules and
tablets are rapidly absorbed once the preparation enters
the small intestine. All the products achieve peak concentrations of approximately 0.5 to
2mg/ml. All of the PPI’s undergo low rates of hepatic first pass metabolism. The absolute
bioavailability of pantoprazole is approximately 77% due to the first pass effect. Omeprazole
shows a saturable first pass effect such that at doses greater than 40mg, the maximum
concentration and the absolute bioavailability are greater than would be expected. NEXIUM
Delayed-Release Capsules contain an enteric-coated pellet formulation of esomeprazole
magnesium. After oral administration peak plasma levels (Cmax) occur at approximately 1.5
hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a
three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40
mg. At repeated once- daily dosing with 40 mg, the systemic bioavailability is approximately
90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole
increases from 4.32 mmol*hr/L on day 1 to 11.2 mmol*hr/L on day 5 after 40 mg once daily
dosing.

Distribution
Protein binding of all the PPI’s is 95% or greater. Rabeprazole, omeprazole and lansoprazole have
been found in the breast- milk of lactating humans. The approximate volume of distribution of
pantoprazole is 11 to 23.6L (mean 0.16L/kg) indicating distribution mainly in the extracellular
fluid, and limited tissue distribution. Omeprazole is found in fetal tissues at concentrations
similar to that achieved in maternal plasma. In animal studies the highest concentrations of
omeprazole were found in the liver, kidneys, duodenum, stomach and thyroid gland following
intravenous administration of omeprazole.
Penetration into red blood cells was found to be low, as well as penetration across the blood-
brain barrier. Following oral administration the stomach and duodenal tissues had the highest
concentrations of omeprazole. The volume of distribution of omeprazole is 0.24L/kg in elderly,
and 0.34-0.37L/kg in adult subjects. The volume of distribution of lansoprazole is
~0.39L/kg. Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant
over the concentration range of 2-20 mmol/L. The apparent volume of distribution at steady
state in healthy volunteers is approximately 16 L.
Metabolism
All of the PPI’s are extensively metabolized in the liver to inactive metabolites. Certain
sub-populations with deficiency of CYP2C19 have been shown to have slow metabolism
of pantoprazole.

Elimination
All of the PPI’s undergo elimination in urine and feces and have elimination halflives of 1.5
hours or less. All of the drugs are cleared mainly as metabolites due to their high degree
of metabolism. Certain slow metabolizers of PPI’s clear the drug more slowly than normal
metabolizers, and have longer drug elimination half-lives.

Side Effects and Precautions

PPIs are generally well tolerated. The frequency of adverse effects associated with PPIs
is similar to that of placebo, with an overall incidence of less than 5 percent11.

The most common adverse effects are headache, diarrhea, abdominal pain, and nausea.
Except for diarrhea, the adverse effects of PPIs do not appear to be related to age,
dosage, or duration of treatment11,12T

he diarrhea seems to be related to the profound acid suppression, which has been shown
to alter the bacterial content of the gut. Nevertheless, the overall incidence of diarrhea
is less than 5 percent, and this effect appears to be dosage and age-related11. Short-
term safety (less than 12 weeks of treatment) of the oldest agents, omeprazole and
lansoprazole, has been well established10. PPIs are only contraindicated if the patient has
a known history of hypersensitivity to them, and they should be used with caution in
patients with severe hepatic disease.

Omeprazole is a pregnancy category C agent; the others are pregnancy category B

medications. PPIs are not recommended for use in breastfeeding mothers13-17.

Drug Interactions
The PPI’s are metabolized by the cytochrome P450 isoenzymes and therefore can be
expected to interact with other drugs that are substrates for that enzyme system.
Omeprazole is, however, the only PPI with known interactions with drugs that are
substrates of the CYP2C19, including diazepam, warfarin and phenytoin. Lansoprazole
interacts with theophylline through CYP1A1 isoenyzme induction. The PPI’s may also affect
the absorption of certain drugs that require an acidic environment for optimal absorption
to occur.
 The drug interactions of the PPI’s are summarized below

Proton Interacting Nature of Interaction

Pump
Drug (s)
Inhibitor
Clarithromycin Increase plasma levels of omeprazole,
clarithromycin and 14-hydroxyclarithromycin
Sucralfate Delayed absorption/Decreas
bioavailability of omeprazole; administer
at least 30 minutes prior to sucralfate.
Diazepam Decrease diazepam clearance 25-50%;130%
increase in half-life and increase plasma
Omeprazole levels of diazepam
Phenytoin 15-20% decrease clearance and 18-25%
increase AUC and 17% increase half-life of
phenytoin.
Warfarin Elimination of warfarin may be prolonged
10% increase in theophylline clearance and 13%
Theophylline decrease in AUC may require dosage
adjustment
Delayed absorption/Decrease
bioavailability of lansoprazole; administer
Sucralfate lansoprazole at least 30 minutes prior to
sucralfate.
Ketoconazole
Lansoprazole
Ampicillin Absorption of these drugs may be decrease by
the change in gastric pH.
esters

Iron salts

It does not significantly affect the kinetics of the drugs as in the case of
Pantoprazole
other PPI’s. In vivo studies, digoxin, ethanol, glyburide, antipyrine, and
caffeine had no clinically relevant interactions with pantoprazole.
 19% increase in digoxin bioavailability, 20%
increase in digoxin
trough levels, 29%
Digoxin
increase in digoxin Cmax
Rabeprazole
Ketoconazole 30% decrease in bioavailability of ketoconazole

Cyclosporine Increase cyclosporine plasma

Levels

Diazepam 45% decrease in clearance of diazepam.

Warfarin Increase in INR and prothrombin time

Esomeprazole
Ketoconazole, iron salts and interfere with the absorption
digoxin

Summary and Conclusion

The proton pump inhibitors are substituted benzimidazoles that inhibit gastric acid secretion
via inhibition of the H+/K+ ATPase pump. Although there are some differences in
pharmacokinetics and binding affinity for the pump, these drugs are comparatively similar in
their efficacy in treatment of gastric diseases. The number of indications for which they are
approved differs, but efficacy has been shown to some extent for most in their non-FDA
approved indications as well, and it is thought that efficacy for all of the indications can be
generalized across the group.

Currently, the PPI’s are the drugs of choice for most gastric acid related diseases because
their efficacy has been proven to be superior to the H2 antagonists. This includes H. pylori
treatment where ≥ 90% eradication can be achieved with a PPI in combination with 2
antibiotics alone. The PPI’s are also considered the treatment of choice for Zollinger-Ellison
Syndrome (ZES). The PPI’s offer convenient once-daily dosing for most indications.
Lansoprazole has the largest number of FDA approved indications of the group and for most of
those indications is more cost effective than the other agents. Lansoprazole can be
administered via nasogastric tube and there is information available regarding administration of
omeprazole via enteral tubes. Omeprazole administration via enteral tubes is more cumbersome
compared with lansaprazole. Pantoprazole has only one indication at this time, and is the most
cost effective of the group for that indication. It also has shown up to this time, no significant
drug-drug interactions, unlike omeprazole which has several significant drug interactions, and
rabeprazole and lansoprazole which each have a few moderately significant drug interactions.
It has shown efficacy in gastric ulcers, duodenal ulcers, and H. pylori eradication in a limited
number of studies, and may become more popular once more safety data is generated. The
PPI’s, as a class are primarily used for a limited duration of time i.e., 4-8 weeks.
 Acknowledgements
A. D.A.V. Public School, ACC Colony, Jamul – 490024, Durg,
Chhattigarh, India (1990 – 2004)
B. University Institute of Pharmacy, Pt. Ravishankar Shukla
University, Raipur, Chhattisgarh, India (2005 – 2009)
C. Shri Rawatpura Sarkar Institute of Pharmacy, Kumhari, Durg,
Chhattisgarh, India (2010 – 2012)
D. Royal College of Pharmacy, Raipur, Chhattisgarh, India (March –
October 2013)
E. National Center for Natural Resources (NCNR), Pt. Ravishankar
Shukla University, Raipur, Chhattisgarh, India (2013 – 2017)
F. Columbia Institute of Pharmacy, Raipur 493111, Chhattisgarh,
India ( 2017 – till date)
G. Gratitude to Resp. Vishal S. Deshmukh Sir (M.Pharm. Supervisor)
H. Gratitude to Resp. Prof. Mitashree Mitra, Dept. of Anthropology,
PRSU, Raipur, Chhattisgarh.
I. Gratitude to Resp. Prof. Atanu Kumar Pati, Vice Chancellor,
Gangadhar Meher University, Sambalpur, Odisha
J. Gratitude to Resp. Prof. Shiv Shankar Shukla Sir, Columbia
Institute of Pharmacy, Raipur 493111, Chhattisgarh, India
(Mentor)