 AWANEX capsule (Esomeprazole magnesium) is a

proton pump inhibitor that responsible for blocking the

final step of acid production.

 Available for oral administration as a delayed released

capsules containing 20 mg, and 40 mg of
Esomeprazole.
 The typical Parietal Cell
H+/K+-ATPase
(Proton
pump)
HCl

Cl-

+H

+K

Acetylcholine Histamine Gastrin

 Esomeprazole, the S-isomer of omeprazole, is the first
proton pump inhibitor developed as a single isomer
(pure isomers of omeprazole) for the treatment of acid-
related diseases.
Event Year
Discovery of proton pump (H+,K+-ATPase) in the secretory 1970
membrane of the parietal cell as the final step in acid secretion
The first nucleus of PPIs (Timoprazole) * 1975
A derivative of timoprazole, Omeprazole, was discovered 1979
omeprazole was taken into Phase III human trials 1982
Omeprazole was launched in 1988 as Losec in Europe, and in 1990 1988
as Prilosec in the United States 1990
Losec became the world's biggest ever selling pharmaceutical product 1996
Fist launch of Lansoprazole in Europe 1991
First launch of Pantoprazole in Germany 1994
First launch of Rabeprazole in USA 1999
First launch of Esomeprazole (S-isomer of Omeprazole) in USA 2000
First launch of Dexlanzoprazole (R-isomer of Lazoprazole) in USA 2009
Studies on timoprazole revealed enlargement of the thyroid gland due to inhibition *
of iodine uptake as well as atrophy of the thymus gland
 All the PPIs available before Esomeprazole are racemic
mixtures of both isomers where S –isomer and the R-
isomer. some times differ markedly in their
.pharmacokinetics and pharmacodynamics
 Omeprazole like other PPIs is a racemic composition of
its two optical isomers, S-omeprazole (esomeprazole)
and R- omeprazole, which have demonstrated
.stereoselective metabolisms
 Only one compound proved superior to omeprazole and
that was the S-isomer, esomeprazole, which was
developed as the magnesium salt.
 The major differences between the R and S forms of
omeprazole relate to their metabolism which accordingly
. reflects of acid inhibition
Properties of PPIs
1. All PPIs are the same family (Benzimidazole
derivatives)

2. All PPIs share the same M.O.A. (PPIs inhibits the

gastric H ＋ , K ＋ -ATPase by covalent bonding
at cysteine's biding sites)

3. All PPIs should be administrated 30-60 min

before food

4. PPIs are prodrugs which activated in acidic media.

Protonation is a mandatory process for PPIs activation.
. All PPIs are prodrugs that require acid-induced activation
After administration, PPIs are absorbed systemically and
. then re-secreted into the canalicular space

 The molecule is converted to its active form -

sulfenamide with exposed sulfur atoms. The exposed
sulfur atoms bind to the sulfur atoms in the cysteine
groups of the proton pump

26
o While the process of activation is generally the
same for each of the PPIs, the protonation and
activation steps are both pH and drug
dependent.

o The five currently available agents differ in rate of

activation, which may impact their onset of
action.

o The rate of acid-induced activation of an individual

PPI depends on the reactivity (i.e., the pKa) of
the molecule 27
 pka
Cysteine
Half-life Bioavailability
binding pKa1 pKa2

Omeprazole 0.5-1 813 and 892 4.06 0.79 35% (30-40)

Esomeprazole 1.5 813 and 892 4.06 0.79 89%

Lansoprazole 1.3-1.7 813 and821 3.83 0.62 %80-85

Pantoprazole 1–1.9 813and822 3.83 0.11 77%

813, 892 and
Rabeprazole 1 – 1.9 4.53 0.62 52%
321

pka1 is indicator for the accumulation of PPIs in parietal

cells. (1st first protonation)
pka2 is the main determinant of activation rate of PPIs.
1.1: Treatment of Gastroesophageal Reflux
Disease (GERD)
 Healing of Erosive Esophagitis
 Esomeprazole is indicated for the short-term treatment (4
to 8 weeks) in the healing and symptomatic resolution of
diagnostically confirmed erosive esophagitis.
 Maintenance of Healing of Erosive Esophagitis
 Esomeprazole is indicated to maintain symptom
resolution and healing of erosive esophagitis.
 Symptomatic Gastroesophageal Reflux
Disease
 Esomeprazole is indicated for treatment of heartburn and
other symptoms associated with GERD.
 1.2: Risk Reduction of NSAID-Associated
) Gastric Ulcer

 Esomeprazole is indicated for the reduction in the

occurrence of gastric ulcers associated with continuous
NSAID therapy in patients at risk for developing gastric
ulcers.
 1.3: H. pylori Eradication to Reduce the Risk
of Duodenal Ulcer Recurrence

 Triple Therapy (Esomeprazole plus amoxicillin and

clarithromycin) is indicated for the treatment of patients
with H. pylori infection and duodenal ulcer disease

 Esomeprazole has exceptional synergistic effect when it

combined with clarithromycin

 Eradication of H. pylori has been shown to reduce the

risk of duodenal ulcer recurrence.
 1.4: Treatment of Laryngopharyngeal reflux
(LPR)

 Esomeprazole is indicated for treatment of LPR as a

basic line of treatment supported with prokientics and
NSAIDs
 Esomeprazole is supplied as delayed-release
capsules for oral administration.

 Esomeprazoleshould be taken at least one

hour before meals..

 The recommended dosages are outlined in he

table below.
2.1: Indication Dose Frequency

Healing of Erosive Esophagitis 40 mg Once Daily for 4 to 8 Weeks*

Maintenance of Healing of 20 mg Once Daily**

Erosive Esophagitis
Symptomatic Gastroesophageal 20 mg Once Daily for 4 Weeks***
Reflux Disease 40 mg
Risk Reduction of NSAID Associated 20 mg or Once Daily for up to 6
Gastric Ulcer 40 mg months**

Pathological Hypersecretory Conditions 40 mg ‡Twice Daily

Including Zollinger- Ellison Syndrome
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy:
Esomeprazole 40 mg Once Daily for 10 Days
Amoxicillin 1000 mg Twice Daily for 10
Clarithromycin 500 mg Days Twice Daily for
10 Days
: Special Populations

 Geriatric

No dosage adjustment is necessary. Of the total

number of patients who received Esomeprazole in
clinical trials, 1459 were 65 to 74 years of age
and 354 patients were ≥ 75 years of age.

No overall differences in safety and efficacy were

observed between the elderly and younger
individuals
 Special Populations

 Renal Insufficiency
No dosage adjustment is necessary.

 Hepatic Insufficiency
No dosage adjustment is necessary in patients with
mild to moderate liver impairment (Child Pugh
Classes A and B).
For patients with severe liver impairment (Child
Pugh Class C), a dose of 20 mg should not be
exceeded
 Specific Populations

 Pregnancy

Pregnancy Category C

USE IS RECOMMENDED ONLY IF CLEARLY

NEEDED AND THE BENEFIT OVERWEIGHS
THE RISK

There are no adequate and well controlled studies

in pregnancy.
 Specific Populations

 Nursing Mothers
 The excretion of esomeprazole in milk has not
been studied. However, omeprazole concentrations
have been measured in breast milk of one woman
taking omeprazole 20 mg per day. The infant
experienced no adverse effects and received 0.9%
of the maternal daily dose.
 Specific Populations

 Pediatric Use
 Use of Esomeprazole in pediatric and adolescent
patients 1 month to 17 years of age for short-term
treatment of GERD is supported by a) extrapolation
of results, already included in the currently
approved labeling, from adequate and well-
controlled studies that supported the approval)
 Esomeprazole is contraindicated in patients
with known hypersensitivity to any component
of the formulation or to substituted
benzimidazoles.
Effects on absorption
Esomeprazole inhibits gastric acid secretion.
Therefore, esomeprazole may interfere with the
absorption of drugs where gastric pH is an important
determinant of bioavailability
(e.g., ketoconazole, iron salts and digoxin).
 Esomeprazole is extensively metabolized in the liver
by CYP2C19 and CYP3A4.

In vitro and in vivo studies have shown that

esomeprazole is not likely to inhibit CYPs 1A2, 2A6,
2C9, 2D6, 2E1 and 3A4.

No clinically relevant interactions with drugs

metabolized by these CYP enzymes would be
expected.

Drug interaction studies have shown that esomeprazole

does not have any clinically significant interactions with
phenytoin, warfarin, quinidine, clarithromycin or
amoxicillin
Esomeprazole is a PPI that suppresses gastric acid
secretion by specific inhibition of the H+/K+-ATPase in
the gastric parietal cell.

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..
After oral administration peak plasma levels occur at
approximately 1.5 hours

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.

Systemic bioavailability is approximately 90% .

The AUC after administration of a single 40 mg dose of
esomeprazole is decreased by 43- 53% after food
intake compared to fasting conditions.

Esomeprazole should be taken at least one hour

before meals.
 7.2:Pharmacokinetics
 Distribution
 Esomeprazole is 97% bound to plasma proteins.

 Excretion
 The plasma elimination half-life of esomeprazole is
approximately 1-1.5 hours.
 Approximately 80% of an oral dose of esomeprazole is
excreted as inactive metabolites in the urine, and the
remainder is found as inactive metabolites in the feces.
 7.2:
Pharmacokinetics
 Metabolism

 Esomeprazole has an advantageous metabolism – less

is cleared through cytochrome P450 2C19 compared
with the R-isomer.

 The metabolism is largely mediated by the two hepatic

cytochrome P450 (CYP) isoforms, CYP2C19 and
CYP3A4.
 7.2:
Pharmacokinetics
 Metabolism

 Following absorption, more Esomeprazole passes

through the liver without being metabolized, and more
compound remains in the bloodstream.

 Delivery of Esomeprazole to the proton pumps of the

gastric parietal cell is thus enhanced compared with
omeprazole.
 Esomeprazole has an advantageous metabolism
that results in higher AUC values, higher
bioavailability consequently better delivery to the
proton pump compared with omeprazole plus more
consistent pharmacokinetics between individuals
compared omeprazole.
 it is the AUC value that determines how much PPI
reaches its site of action, the proton pump of the gastric
parietal cell, and hence the control of acid secretion

 This is the underlying rationale for the superior acid

control seen with Esomeprazole compared with all other
PPIs.
 . First-pass metabolism decreased

 Systemic clearance decreased.

 Enhanced delivery to the site of action.

 Inhibition of more gastric proton pumps.

 Higher pka1 value Highest pKa2

value

+ Superior acid control Superior onset of action

: Main Indications
I. Treatment of Symptomatic Gastroesophageal
Reflux Disease (GERD)
II. Healing of Erosive Esophagitis
III. Maintenance of Healing of Erosive
Esophagitis
IV. H. pylori Eradication to Reduce the Risk
of Duodenal Ulcer Recurrence
V. Risk Reduction of NSAID-Associated
Gastric Ulcer)
VI. GERD & Heartburn during pregnancy
VII. Reflux laryngio-pharyngitis
Attributes Functional benefits Emotional benefits

Higher pKa2 value Faster activation thus Rapid relief of

faster onset of action symptoms
and results satisfy patient's
need
Higher Bioavailability, AUC Better accumulation in Better prognosis and
& pKa1 the partial cells so better quality of life
better blockage of PP (patients restores
for more longer periods their quality of sleep,
life and appetite)
accordingly superior Reduce treatment
acid suppression cost and duration with
less dose overburden
So better healing rates Ensures patient’s
Truly once daily what compliance
ever the case.
Oral and I.V. form Flexibility in switching Ensures
availability even for infusion between forms physicians
or injection within the same compliance
brand.
Attributes Functional benefits Emotional benefits
Less defendant on CYP2C19 Relatively less Ensures physicians
incidence of drug compliance
interaction with less
inter patient variation Of choice for poly
medicated patients
and multicultural
communities

Has a synergistic action Improve the prognosis Reduce the patient’s

with Clarithromycin in Pylori eradication and physician's fears
and treatment from recurrence risk
Has a huge numbers of Physicians confidence
landmark clinical trials that will be evidence
confirm superiority over based and driven by
other PPIs patients feedback

Competitive quality with Achieve Cost benefits

competitive price effectiveness equation
Claim Counteract
Golden standard and time tested ESOMEPRAZOLE is the pure S isomer of the
molecule same molecule that will maintain all the
positives plus

All PPIs are same in mg equivalent Batter pharmacokinetic profiles with impressive
doses AUC that exceed omeprazole from 180% up to
500%

Better acid suppression, healing Which ultimately translated to superior acid

rates and relief of heartburn suppression, healing rates moreover in shorter
treatment duration.
Claim Counteract
The fastest acting PPI The relatively high (non significant absorption time) may
for rapid results based give advantage over Pantoprazole or Rabeprazole however
on the rapid absorption it’s clinically not proved for:
and high pKa 2
1 - The main determinant for PPIs onset of action is
pKa1 and pKa 2 as the product may absorbed rapidly but
take very long time either in accumulation or waiting
activation
2 - Lansoprazole has the lowest pKa1 which is the main
determinant for accumulation in the site of action (Parietal
cells) moreover lansoprazole binding 321 cysteine binding
sit which is shallow binding sit.
that may justify the relatively week antisecretory activity
when compared to other PPIs or the double dose that
required to achieve required results when compared to
Esomeprazole normal dose

3 - Lansoprazole has less pKa2 compared to

ESOMEPRAZOLE which will guarantee the faster
activation rate and onset of action for esomeprazole that
even confirmed by clinical trials
Claim Counteract
Less inhibitory 1-There is no strong clinical trial support that Pantoprazole has
effect for CYP450 more acid suppression or even longer acid suppression or
for less drug even better healing rate more than ESOMEPRAZOLE
interaction

2 - Most of PPIs like Omeprazole or lansoprazole or even

Esomeprazole are time tested which confirming that the there
is no significant drug interaction which make them inferior
to Pantoprazole safety wise

3- The main weakness of Pantoprazole is week

pharmacokinetic profile (very low pKa1, pKa2 and
Bioavailability) that leads to extreme delay in the onset on
action and relief which makes Pantoprazole not the drug of
choice for GERD or symptomatic heartburn patients whom
seek rapid onset of relief
Claim Counteract
The fastest PPI ever Basically pKa1 value is indicative for the drug accumulation
based on highest which confirm that Rabeprazole will have the higher
pKa1 value accumulation vs Lanzo and Panto However the difference is
not that much vs Eso. moreover one important factor affecting
Ideal for GERD and on the accumulation as well which is Bioavailability the
demand therapy determinant of availability of drug which will be accumulated
later. Rabeprazole has the lowest Bioavailability 52% after
omeprazole

2- while the main indicative for activation and onset of action

is pKa2 and tmax where’s Rabeprazole has lower pKa2
value vs Esomprazole and has the lowest tmax 3-5 H.
3- Despite there is no head to head comparative clinical trials
regarding healing but the available clinical trials regarding PH
holding time above 4 confirming the superiority of
ESOMEPRAZOLE accordingly
Less dependent It may be consider as edge for Rabeprazole over OME and
on CYP2C19 LANZO but not over Esomeprazole as the later is less
dependent on CYP2C19 as well
 Not all PPIs are the same
Pharmacodynamics differences among PPIs could
translate into and justify the clinical
difference.

1. Activation time of PPIs

2. Accumulation of PPI in the parietal cell,
3. Metabolism of PPI. And Area under curve.
4. The difference in onset of symptoms relief
5. Degree of acid suppression (PH level and
holding time)
6. Healing rates and time.
 The efficacy of PPIs on acid suppression is directly related to AUC,
Which determine how much of PPIs reach parietal cell (6)

 AUC values, for esomeprazole, 20 mg, is about 180% of that for omeprazole, 20 mg.
while for esomeprazole, 40 mg, is more than 500% greater than that for omeprazole