Rabeprazole 20 mg +

Itopride ER 150 mg
Dr Amita Birla
The normal gastric mucosa
Cardia – mainly
mucus-secreting cells

Fundus (body) – acid

producing parietal
cells, pepsin
producing chief cells

Pylorus – hormone
(gastrin) production
 Acid Peptic Disease
Group of disorder due to harmful effect of
acid and pepsin on GI mucosa
Dyspepsia: Pain or discomfort centered in the
upper abdomen, upper abdominal fullness,
early satiety, bloating, or nausea

Zollinger Ellison Syndrome: A small tumor in

the pancreas or small intestine producing
excess gastrin
 Ulcers
Therapy is directed at enhancing host defense or
eliminating aggressive factors; i.e., H. pylori.

Aggressive Factors Defensive Factors

 Acid, pepsin  Mucus, bicarbonate layer
 Bile salts  Blood flow, cell renewal
 Drugs (NSAIDs)  Prostaglandins
 H. pylori  Phospholipid
 Free radical scavengers
 Overlapping Symptoms of
Acid-peptic disease
Heartburn

Regurgitation

Belching

Nausea

Post- prandial bloating

Treatment
 Proton Pump Inhibitors:
Mechanism of Action
Block the H+,K+-ATPase enzyme of the
parietal cell

Inhibit gastric acid secretion

More effective than H2 antagonists as they

block the final step in acid secretion
 Proton Pump Inhibitors
First generation
Omeprazole

Lansoprazole

Pantoprazole

Second generation
Esomeprazole

Rabeprazole
Disadvantages of First Generation PPIs
Slow onset of action

Interpatient variability common

Significant drug interactions

Food affects pharmacokinetics

Fail to provide 24-hour suppression of gastric acid

 Mechanism of action
In parietal cell

Rabeprazole is ionized

Active sulfenamide form

Binds with cysteine of proton pump

Inhibits acid secretion

 Action
Compared with omeprazole, esomeprazole, lansoprazole
and pantoprazole, rabeprazole is less dependent on low pH
for conversion to its active form

Because rabeprazole is less dependent on low pH for its

activation, subsequent doses can continue to bind and inhibit
the pump at higher pH levels, resulting in early sustained
acid suppression compared with other proton pump inhibitors
Aliment Pharmacol Ther 2004; 20 (Suppl. 6): 30–37.
 Action
Besides its rapid and prolonged effect
on acid secretion, rabeprazole has
been demonstrated to significantly
enhance gastric mucin content

Dig Dis Sci 2003; 48: 322–8.

 Rabee

FAST RELIEF

EVEN FASTER
 Pharmacokinetics
Bioavailability 52%
C max- 0.407 mcg/ml
T max- 2-5 hrs, Reduced with sodium
buffer
PPB 96%
Metabolism Mainly by non-enzyme systems,
Minor metabolism by CYP 2C19
and CYP 3A4 – no inter-patient
variability.
t1/2 1-2 hours

Effect of food Food delayed T max by 1.7 hrs

without affecting AUC or C max
 Indications
GERD therapy
Erosive oesophagitis
Short-term treatment of active duodenal
and benign ( not malignant) gastric ulcers
Zollinger-Ellison syndrome
Treatment of H. pylori–induced ulcers
Dosage and Administration
Healing of GERD
20 mg OD 4 weeks

Maintenance of healing of GERD

20 mg OD as long as clinically indicated

Healing of Gastric & Duodenal Ulcers

20 mg OD for 4 weeks in duodenal ulcer
20 mg OD for 6 weeks in gastric ulcer

Drugs 2001; 61 (15);

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 Dosage and
Administration
Treatment of Zollinger – Ellison Syndrome
60 mg OD till clinically indicated

Helicobacter Pylori Eradication-

Rabeprazole 20mg/day with
Clarithromycin 500mg BID and
Amoxycillin 1gm BID for a period of 7 days

Drugs 2001; 61 (15);

2327-2356
 Drug Interactions
Does not interact with the
Cytochrome P450 system , no drug
interactions

Drugs 2001; 61 (15);

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 Adverse Effects
 Headache
 Diarrhoea

 Rhinitis

 Nausea

 Pharyngitis

Abdominal pain

Drugs 2001; 61 (15); 2327-2356

 Rabeprazole Vs
Rabeprazole
Omeprazole
Omeprazole
2nd generation PPI
Rapid onset of action
Maximal effect with first dose
Less drug interactions
Efficacy not affected by
CYP2C19 genotype
H.pylori eradication rate- 84%
Median 24hr intra-gastric pH is
3.4
1st generation PPI
Slow onset of action
Maximal effect not seen with
first dose
More drug interactions
Efficacy affected by CYP2C19
genotype
H.pylori eradication rate-69%
Median 24hr intra-gastric pH is
1.9
Drugs 2001; 61 (15);
2327-2356
 Rabeprazole vs Esomeprazole
Rabeprazole Esomeprazole
Greater anti- Lesser anti-
secretory effect secretory effect
Less drug More drug
interactions interactions
Gastric pH more Gastric pH more
than 4.0 for 56% than 4.0 for 43%
time during time during
treatment treatment
S.Warrington et al Aliment Pharmacol Ther 2002;16:1301-1307
 USP
Second generation PPI
Fastest acting PPI
Fastest symptom relief from Day 1
93% healing rates in GERD
98% healing rates in Peptic Ulcers
Convenient OD dosage, absorption unaffected
by food
Excellent safety profile
Least Drug-Drug interactions
Active over wide range of PH
Increases Mucin Secretion
Rabee
 Trial
Design: A randomized, placebo-controlled trial of 203 patients
with nonerosive gastroesophageal reflux disease (GERD)

Study Group: Rabeprazole 10 milligrams (n=65) or 20

milligrams (n=68) daily for four weeks

Results:
Rabeprazole was superior to placebo (n=70) in the relief of
GERD-related heartburn.

Other GERD-related symptoms, including regurgitation,

belching and nausea were also improved with therapy.

There was no significant difference in the incidence of

adverse effects among the three treatment groups (Miner et
al, 2002).
 Trial
Rapid symptomatic relief of the major complaints of
daytime or nighttime HEARTBURN was demonstrated in an
open-label evaluation of nearly 2500 patients.

After the first day, complete relief of heartburn was

claimed by 64% to 69%, and after 1 week by 85%.

Neither age nor gender, initial severity (Hetzel-Dent grade)

of esophagitis or presence or absence of Barrett's
esophagus effected response rates (Robinson et al, 2002).
 Trial
Symptom relief (daytime or nighttime
heartburn) was similarly rapid and extensive
when standard dose rabeprazole (20
milligrams (mg)) was compared to high-dose
(40 mg) omeprazole in 250 patients with
endoscopically confirmed erosive esophagitis.

By day 4, 84% of patients in either group were

asymptomatic (range 75% to 90%)
 Trial
However, the proportion of patients rating
symptoms as "severe-to-very-severe", particularly
during the first 3 days of treatment, were nearly
twice as frequent among omeprazole users
(10.3% versus 4.7%) for both daytime and
nighttime heartburn.

Endoscopic confirmation of healing was slightly

higher among rabeprazole users at 8 weeks for
both Helicobacter-positive patients (92.7% versus
89.2%) as well as those with grade III GERD(88%
versus 78%) (Holtzman et al, 2002).
Itopride
GI conditions where Dysmotility is
associated with Acidity
GERD

Gastroparesis

Functional Dyspepsia or Non-ulcer Dyspepsia

* Delayed gastric emptying due to damage to vagus nerve

**Muscles of the GIT organs or the nerves that control the GIT organs are
not working normally
Gastroesophageal Reflux Disease
(GERD)
Any symptoms or esophageal mucosal damage that results
from reflux of gastric acid into the esophagus

Classic GERD symptoms

 Heartburn (pyrosis): substernal burning discomfort

 Regurgitation: bitter, acidic fluid in the mouth when lying

down or bending over
 Gastroparesis
Disorder in which stomach takes too long to empty its
contents

Also called delayed gastric emptying

Due to damage to vagus nerve muscles of stomach and

intestine do not work properly

Cause – surgery on stomach, trauma, diabetes

Functional (Non-ulcer) dyspepsia
Group of disorders associated with
abdominal pain without presence of ulcer

Muscles of the organs or the nerves that

control the organs are not working normally

No structural lesion can be detected e.g.

hypothyroidism, diabetes etc.
 PROKINETICS
drugs increasing GIT motility
These drugs increase:
 Tonus of the lower oesophageal sphincter (inhibition of
gastro-esophageal reflux)
 Gastric emptying (improve gastroparesis and functional
dyspepsia)
 intestinal motility (increased peristalsis)

Mechanisms of Action
 Antagonism at D2 receptors – desinhibition of myenteric
motor neurons leads to the increased ACh release
 Modulation of 5-HT receptors (5-HT4, 5-HT1) – complex

effects resulting in increased ACh release (among

others)
 Prokinetics
Domperidon
Mechanism of action: predominantly a D2-antagonist
 It does not cross the blood-brain barrier
(hence no extrapyramidal adverse effects)
But it affects those CNS areas which lack the barrier
- area postrema (antiemetic action )
- hypophysis (prolactin secretion )
Adverse reaction: galactorrhea, gynecomastia, amenorrhea
Metoclopramide
Mechanism of action is more complex: D2-antagonism,
5HT4 receptor agonism, sensitisation of M receptors
- antiemetic action
- CNS adverse effects: extrapyramidal (parkinsonian-like
symptomes)
Itopride - D2-antagonist/Acetylcholinesterase inhibitor
 Prokinetics
(Cisaprid) Just for your information:
Mechanism of action: an agonist on 5-HT4 receptors
It was quite potent and often used drug!
It was recently withdrawn in number of countries due to the
increased risk of arrhythmias - „torsades de pointes“
The name means „twisting of the points“ in French, referring
to the characteristic appearance of the electrocardiogram
during the rhythm abnormality.
- It is uncommon polymorphous ventricular tachyarrhythmia
with potentially fatal outcomes (associated with long QT-
interval)
 Itopride
Itopride hydrochloride improves gastro-intestinal
motility by a dual mode of action.

First, it enhances the release of acetylcholine in

the myenteric plexus by antagonising the action
of dopamine on the D2-receptors on the
postsynaptic cholinergic nerves;

Secondly, it prevents hydrolysis of the released

acetylcholine by the enzyme acetylcholinesterase
in the smooth muscle of the upper gastro-
intestinal tract.
 Itopride
This dual mode of action differentiates itopride
from the available prokinetics such as
metoclopramide and domperidone.

Moreover, itopride has no affinity for the 5-HT4

receptors, unlike cisapride and mosapride, which
are 5-HT4 agonists. The affinity of cisapride for 5-
HT4 receptors in the heart has been implicated in
the undesirable cardiac effects of the drug.
 Study-Diabetic Gastroparesis
Prokinetics are effective in improvement of delayed
gastric emptying, which leads to better glycemic
control in diabetic patients.

Through the mechanism of how prokinetics act on

gastric electrical events, improvement of delayed
gastric emptying in patients with autonomic
neuropathy should be achieved, not only for the relief
of GI symptoms but also for stable glycemic control
Diabet Med. 1993;10 Suppl 2:79S-81S
 Trial-Dyspepsia
Aim: To document the clinical efficacy and
tolerability of itopride hydrochloride in
patients with non-ulcer dyspepsia

Design: An open-label, non-comparative

study, was undertaken at the Medical College,
Thiruvananthapuram, among patients with
endoscopically confirmed diagnosis of non-
ulcer dyspepsia or chronic gastritis.
 Trial
Method:
Itopride hydrochloride 50 mg (1 tablet) thrice a
day for 2 weeks was administered among them.

Relief of symptoms at the end of two weeks

treatment, assessed as marked/complete,
moderate, slight, none or worse; QT interval on
ECG; adverse events; haemogram; serum
chemistry for hepatic and renal functions.
 Trial
Results:
At the end of 2 weeks' treatment, moderate to
complete relief of symptoms was reported by 22
patients (73%), whereas 5 (17%) reported slight
improvement, and 3 (10%) reported no improvement.
Clinical tolerability was excellent in 28 patients (93%)
and good in 2 (7%).
None of the patients had any prolongation of QT on
ECG, nor did any patient show any abnormality in
haemogram or serum chemistry during the treatment.
February 23, 2006 Study - Itopride shows symptom
improvement in functional dyspepsia

Conclusions Treatment with Itopride significantly reduced the

number of symptoms in patients with functional dyspepsia
according to a double blind, placebo-controlled trial reported in
the New England Journal of Medicine.

Methods German researchers randomized 523 patients (63.5%

female) with a mean age 47.9 years with functional dyspepsia,
to receive oral itopride either 50 mg, 100 mg, or 200 mg or
placebo three times daily. Symptom analysis was conducted
after eight weeks of double-blind treatment.
 Rabee Itopride
The Ultimate Solution
 Indications
GERD

Gastroparesis

Functional (Non-ulcer) Dyspepsia

 Salient Features of Rabee-
Itopride
Right combination of a potent PPI with a
potent GI prokinetic agent

Faster and 24 hour symptomatic relief in

Acid peptic disorders

Once a day administration, hence improved

compliance
 Salient Features of Rabee-
Itopride
Onset of action is very quick

Itopride does not produce extrapyramidal side effects

as it does not cross BBB

No significant adverse reaction on CVS system

Superior acid supression and longer duration of action

No inter patient variability

Drugs 2001; 61 (15); 2327-2356

 Dosage
1 capsule once daily before food
Rabe (Enteric Coated)-20 mg
Itopride (Sustained Release)- 150 mg
 Precaution and CI
Hypersensitivity

Lactation

It should be used with caution in

patients with severe hepatic impairment
and in pregnancy
 Interactions
Rabeprole increases eliminationT ½ of
digoxin, decreases effects with amino
glutethimide, carbamazepine, phenotoin
and rifampin and reduces aborption of
ketoconazole and itracnazole.

Anti cholinergic agents reduces the

action of Itopride
 Adverse Reaction
Headache, diarrhoea, dizziness,
rash.

Potential Life threatening:

Anaphylaxis, agranulocytosis
 Summary
Itopride by increasing acetylcholine
concentrations by inhibiting dopamine D2
receptors and acetylcholinesterase,
Increases GI peristalsis,
Increases the lower esophageal sphincter
pressure,
Stimulates gastric motility,
Accelerates gastric emptying,
Improves gastro-duodenal coordination
Thus decreases the amount of reflex.
 Summary
On other hand Rabeprazole reduces the
damage to the esophagus lining by
suppressing the gastric acid secretion by
inhibiting the gastric H+K+ATPase at the
secretory surface of the gastric parietal cell.

Moreover, Rabeprazole and SR Itopride are

given as once a day dosage and thus ideal
for combination.
Peptic ulcer disease: shifting out of the main interests
of surgery into the main interests of gastroenterology
Thank you…