Gastric Acid Disorders
Effective treatment
using Rabeprazol
Dr Anshu P Gokarn MBBS, MD(Pharmacology)
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – proton pump
inhibitors
5. Rabeprazol
22 Dr Anshu P Gokarn
Part 1
Part 2
Part I
3 Dr Anshu P Gokarn
Gastric Acid Disorders
Effective treatment
using Rabeprazol
Dr Anshu P Gokarn MBBS, MD(Pharmacology)
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – proton pump
inhibitors
5. Rabeprazol
44 Dr Anshu P Gokarn
Stomach
Main Functions
Storage
Preparing the chyme for digestion in the
small intestine
Absorption of water and lipid-soluble
substances (alcohol and drugs)
55 Dr Anshu P Gokarn
Stomach
66 Dr Anshu P Gokarn
Stomach
Types of Gland (located in gastric mucosa):
Cardiac Glands
Pyloric glands (many G cells)
Oxyntic glands (most abundant, found in
fundus and corpus)
77 Dr Anshu P Gokarn
Chief Cell
Surface Mucous Cell
Mucous Neck Cell
Panetal Cell
Endocrine Cell
Isthmus
Gastric Pit (Ioveola)
Oxyntic Gland
Neck
Base
88 Dr Anshu P Gokarn
Stomach Cells
Types of Cells
Parietal cells
most distinctive cells in stomach (HCl &
intrinsic factor)
Chief cells
pepsinogen
Mucus neck cells:
- HCO3-
- Mucus
99 Dr Anshu P Gokarn
Types of Cells
G Cells: Gastrin (hormone) ---> HCl secretion
D Cells: Somatostatin (antrum)
Enterochromaffin-like cell: Histamine
1010 Dr Anshu P Gokarn
Types of Cells
1111 Dr Anshu P Gokarn
Gastric juices
HCl (hydrochloric acid)
Pepsinogen
Electrolytes
Intrinsic factor
Mucus (mucus gel layer)
pH ~4
1212 Dr Anshu P Gokarn
Gastric motility
Functions
1. Allows the stomach to serve as
reservoir
2. Breaks food to small particles and mix
it with gastric juice
3. Empties gastric contents at a
controlled rate
1313 Dr Anshu P Gokarn
Gastric motility
Reservoir part
fundus + 1/3 corpus
(tonic contraction)
Antral pump
2/3 corpus + antrum & pylorus
(phasic contraction)
1414 Dr Anshu P Gokarn
1515 Dr Anshu P Gokarn
Gastric motility
Anatomic Regions Functional Motor
Regions
Mixing & emptying of gastric contents
Gastric contents may remain unmixed (1h)
Fat takes a longer time for empty
Liquids are emptied easier and first
Major mixing activities are in the antrum
Retropulsion
1616 Dr Anshu P Gokarn
1717 Dr Anshu P Gokarn
Mixing & emptying of gastric contents
1818 Dr Anshu P Gokarn
Constriction of pyloric sphincter
Constriction of pyloric sphincter
Hormones promote constriction
1. CCK
2. Secretin
3. Gastrin
4. GIP
Sympathetic innervation
1919 Dr Anshu P Gokarn
Regulation of gastric emptying
Acidity (stomach) Secretin antral contraction
Fat (monoglycerides) CCK, GIP gastric emptying
Hyperosmotic solutions gastric emptying
Amino acids G cells Gastrin contraction of sphincter
2020 Dr Anshu P Gokarn
2121 Dr Anshu P Gokarn
Gastric reservoir
Functions:
To maintain a continuous compression
To accommodate the received food with
out significant gastric wall distention or
pressure
2222 Dr Anshu P Gokarn
Receptive relaxation
- triggered by swallowing reflex
Adaptive relaxation
- triggered by stretch receptors (vago-vagal
reflex)
- lost in vagotomy
- threshold of fullness and pain
Feedback relaxation
- triggered by chyme in small intestine
Relaxation in gastric reservoir
2323 Dr Anshu P Gokarn
Gastric juices
HydroChloric Acid (HCl) Secretion
Secreted by parietal cells
Fundus
Body
2424 Dr Anshu P Gokarn
Gastric juices – HCl Secretion
2525 Dr Anshu P Gokarn
HCl Secretion (cont)
Mechanism of HCl production:
H/K ATPase
Inhibited by: omeprazole
H/K pump depends on [K]out
[HCl] drives water into gastric content to
maintain iso-osmolality
During gastric acid secretion:
amount of HCO3- in blood = amount of HCl
being secreted
Alkaline tide
2626 Dr Anshu P Gokarn
Neural & Hormonal Control of Gastric
Secretion
Vagus nerve (neural effector)
Gastrin (hormonal effector)
Enterochromaffin-like cellsHistamine ---
H2 receptor (parietal cells) acid secretion
Cimetidine (H2 receptor blocker) peptic ulcer and
gastroesophageal reflux
2727 Dr Anshu P Gokarn
2828 Dr Anshu P Gokarn
Neural & Hormonal Control of Gastric
Secretion
Neural & Hormonal Control of Gastric
Secretion
2929 Dr Anshu P Gokarn
Phases of Acid Secretion
Cephalic phase(30%): Smelling, Chewing and swallowing
Stimulates parietal G-Cells
GRP
Gastric phase (60%): gastric distention
proteins
Intestinal phase (10%):
digested proteins
3030 Dr Anshu P Gokarn
Regulation of Acid Secretion
3131 Dr Anshu P Gokarn
Inhibition of Acid Secretion
Inhibitory hormones (Enterogastrones):
Somatostatin (D-cells) in antrum
Secretin (S-cells) in duodenum
Glucose-dependent insulinotropic peptide
(GIP) in duodenum
3232 Dr Anshu P Gokarn
Mechanism of gastric acid secretion
Gastrin Histamine
Acetylcholine
Ca2+
HCI
Protein kinases Protein kinases Protein kinases Protein kinases
Ca2+ Ca2+
Release of Ca2+ from
intracellular stores
Release of Ca2+ from
intracellular stores
cAMP cAMP
Protein
kinases
Protein
kinases
Release of Ca2+ from intracellular stores
Release of Ca2+ from intracellular stores
ACh (M3)
Ca2+ Ca2+
H
K
K
Cl
Cl
HCl
AcidAcid pumppump
3333 Dr Anshu P Gokarn
3535 Dr Anshu P Gokarn
Activation of H1K ATPase
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – proton pump
inhibitors
5. Rabeprazol
3636 Dr Anshu P Gokarn
Aspirin and other NSAIDs
PROTECTIVE FACTORS
Mucus layer
Ionic gradient
Bicarbonate layer
Prostaglandins
Surface epithelial cells
Mucosal blood supply
H. pylori Pepsin Gastric
acid
AGGRESSIVE FACTORS
Aspirin and other NSAIDs
Prostaglandin production
Bicarbonate production
Mucus production
Acidic environment
Neutral environment
Gastric acid plays a central role in
NSAID-associated gastroduodenal damage
3737 Dr Anshu P Gokarn
Helicobacter pylori
3838 Dr Anshu P Gokarn
IL-8
Proteolytic
enzymes
O2 radicals
Infection with H. pylori results in an
acute inflammatory reaction
Epithelial cell
Polymorph
3939 Dr Anshu P Gokarn
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – proton pump
inhibitors
5. Rabeprazol
4141 Dr Anshu P Gokarn
Gastroesophageal reflux disease
4242 Dr Anshu P Gokarn
Gastroesophageal reflux
disease (GERD) is a chronic,
relapsing condition with
associated morbidity and an
adverse impact on quality of
life. The disease is common,
with an estimated lifetime
prevalence of 25 to 35
percent.
4343 Dr Anshu P Gokarn
Gastroesophageal reflux disease
An approximated 2% of
the adult population
suffer from GERD all
over the world.
The incidence of GERD
increases markedly
after the age of 40.
Dr Anshu P Gokarn 46
Gastroesophageal reflux disease
Complications of GERD
Barrett’s esophagus
Esophageal strictures
Carcinomas
Barrett’s esophagus
Gastric Cancer Esophageal strictures 4747 Dr Anshu P Gokarn
Lifestyle modification should be initiated and
continued throughout the course of GERD
therapy
Antacids and over-the-counter acid
suppressants are appropriate, initial patient-
directed therapy for GERD.
Acid suppression by PPIs which provide
symptomatic relief and healing of esophagitis
Guidelines for management of GERD
DeVault RK et al,The American Journal of Gastroenterology 1999:94(6): 1434-42
5252 Dr Anshu P Gokarn
Guidelines contd.
Chronic proton pump inhibitor therapy is an
effective and appropriate form of maintenance
therapy in many patients.
Antireflux surgery, performed by an
experienced surgeon, is a maintenance option
for the patient with well-documented GERD.
DeVault RK et al,The American Journal of Gastroenterology1999:94(6):1434-42
5353 Dr Anshu P Gokarn
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD
5. Proton Pump Inhibitors - Rabeprazol
5454 Dr Anshu P Gokarn
Proton-pump inhibitors (PPIs) - pronounced and long-
lasting reduction of gastric acid production
Most potent inhibitors of acid secretion available.
Largely superseded another group of pharmaceuticals
called H2-receptor antagonists.
Biological target Hydrogen potassium ATPase
Proton pump inhibitors
5757 Dr Anshu P Gokarn
Proton pump inhibitors
5858 Dr Anshu P Gokarn
End of Part – I
any questions ?any questions ?
Part II
59 Dr Anshu P
Gokarn
Gastric Acid Disorders
Effective treatment
using Rabeprazol
Dr Anshu P Gokarn MBBS, MD(Pharmacology)
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – proton pump
inhibitors
5. Rabeprazol
6060 Dr Anshu P Gokarn
Part 1
Part 2
MODERN ZEN
6161 Dr Anshu P Gokarn
Rabeprazole
• Novel Proton pump inhibitor
• Acid suppression with once-daily dosing
• Consistent symptom control
• Significantly effective healing rates in erosive
GERD.
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
6262 Dr Anshu P Gokarn
Chemistry
Substituted benzimidazole sulfoxide
Empirical Formula C18H20N3NaO3S
Molecular weight 381.43
6363 Dr Anshu P Gokarn
• Produrg
• Transformed at low pH to a more reactive
species, a Sulfenamide.
• Sulfenamide reacts with thiol group on
gastric (H+K+)-ATPase.
Structure activity relationship
Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of Substituted
2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992
6464 Dr Anshu P Gokarn
Reduced side effect profile
• Irreversible disulphide bond with the enzyme
(ATPase)
• Binding to the Proton Pumps is partially
reversible.
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
6565 Dr Anshu P Gokarn
Pyridine nitrogen and the nitrogen near
benzimidazole 2-position – responsible for
the activity of rabeprazole.
Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of
Substituted 2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992
6666 Dr Anshu P Gokarn
Pharmacokinetics
Peak plasma levels occur 2-5 hours
after oral administration
Oral bioavailability is approximately
52%.
Plasma elimination half life is 1-2
hours
6767 Dr Anshu P Gokarn
Rapid onset of action
Rapid dissociation to active tetracyclic
sulfenamide.1
Faster Rate of inhibition of proton pump
Faster and greater effect on the
intragastric pH2.
1. Besancon M, Simon A, Sachs G, Shin JM,.Sites of reaction of th egastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997;272(36):22438-22446c
2. Langtry HD, Markham A.Rabeprazole :A review of its use in acic related gastrointestinal disorders. Drugs 1999;58(4):725-742
68 Dr Anshu P Gokarn
To produce the same degree of inhibition
Rabeprazole takes 5 minutes
Omeprazole takes 30 minutes,
Lansoprazole takes 30 minutes,
Pantoprazole takes 60 minutes
Besancon M, Simon A, Sachs G, Shin JM,.Sites of reaction of th egastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem
1997;272(36):22438-22446c
Faster acid inhibition
6969 Dr Anshu P Gokarn
Activation time
Activation time
(minutes)
pH 1.2
pH 5.1
1.3
7.2
Percent inhibition of
the H+/K+-ATPase
At 10 minutes
At 45 minutes
100%
100%
At pH 5.1,the
activation time
is faster for
rabeprazole
compared to
other proton
pump
inhibitors.
7070 Dr Anshu P Gokarn
Increases gastric mucin
Omeprazole reduces gastric mucin and
prevents mucin synthesis
Lansoprazole that has no effect on mucin,
Rabeprazole significantly increases
gastric mucin.
and thus rapid ulcer healing
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
7171 Dr Anshu P Gokarn
Antisecretory potency of Rabeperazole
Vs Omeprazole
Significantly greater decrease in intragastric
acidity over the 24-hour period
Significantly low Intragastric acidity at night and
during 3 of 4 meal related periods
American Pharmaceutical Assoc.,Special Report:The use of proton pump
inhibitors in acid-peptic Disorders 1999
7272 Dr Anshu P Gokarn
331
160
640
218
0
200
400
600
800
Intr
ag
as
tric
ac
idit
y
mm
ol.h
/L
Rabeprazole Omeprazole
Faster onset of antisecretory activity than
Omeprazole
Intragastric acidity -Day 1 Intragastric acidity- Day 8
7373 Dr Anshu P Gokarn
Most Patients Treated With Rabeprazole Reported
Day And Night time Symptom Relief After One Day
No. of patients treated : 2,500
Data presented at the American College of Gastroenterology (ACG) meeting, Oct 16 2000
significantly improved symptoms of both daytime and nighttime heartburn after the first day.
80 % patients with moderate to severe symptoms reported satisfactory symptom relief on day one for both daytime and nighttime heartburn.
By day seven,
91.2 % patients reported satisfactory symptom relief for daytime heartburn,
91.7 percent reported satisfactory symptom relief for nighttime heartburn.**
7474 Dr Anshu P Gokarn
•Calabrese et al. studied the effect of a 3-day course of antibiotics including azithromycin used either at the initiation of 7 days of PPI therapy or at the conclusion of the PPI treatment.
Cure Rate was:
86% (antibiotics at the initiation of PPI therapy)
88% (antibiotics at the end of PPI therapy)
Calabrese C, DiFebo G, Areni A, Scialpi C, Biasco G, Miglioli M. Pantoprazole, azithromycin and tinitazole: short duration triple therapy for eradication of Helicobacter pylori infection. Aliment Pharmacol Ther. 2000;14(12):1613-1617.
Rabeprazole
Short Course Therapy
7575 Dr Anshu P Gokarn
Intrinsically greater reduction in
gastric acid secretion
Intrinsic specificity advantage (binds
to proton pump)
Advantage over H2 antagonists
Yun Hee jang, Hojing Kim; Quantam Chemical study of proton pump inhibiting activity of Substituted
2-Sunfinylbenimidazoles; Korean Jour. Of Med. Chem., VOl 2, No. 2, 1992
7676 Dr Anshu P Gokarn
Does not suppress collagen regeneration
unlike H2 receptor antagonists
Does not delay healing of gastric lesions.
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
Increases Collagen regeneration
7777 Dr Anshu P Gokarn
Pharmacological advantages
over older PPI’s
More potent than other PPI’s
Faster onset of action due to quicker
dissociation.
Complete inhibition of H+K+ATPase.
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
7878 Dr Anshu P Gokarn
Greater increase in mucin synthesis.
Significantly greater anti H. pylori activity.
Does not produce conformational changes in
proton pump
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
Pharmacological advantages over
older PPI’s contd…
7979 Dr Anshu P Gokarn
Does not alter prostaglandin levels
Increases prostaglandin synthesis
Prevents stress induced increase in gastric
mucosal peptide –leukotriene
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
Does not alter testosterone levels
NoNo effecteffect onon steroidogenesissteroidogenesis unlikeunlike omeprazoleomeprazole
8080 Dr Anshu P Gokarn
Indications
Duodenal ulcer
GERD
Gastric ulcer
Reflux oesophagitis
Zollinger- Ellison Syndrome
H. pylori eradication
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
8181 Dr Anshu P Gokarn
Consistent symptomatic
relief
More consistent symptomatic relief H2
receptor antagonists or other PPIs
Superior to omeprazole and ranitidine in
prevention of symptoms in patients with
healed GERD.
Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
8282 Dr Anshu P Gokarn
Nocturnal symptom relief
Greater reduction in frequency and severity
of symptoms especially nighttime heartburn.
Significantly lower Intragastric acidity at
night. 1
Nocturnal acid control consistent after 8
days of once daily doses.2
1. American Pharmaceutical Assoc.,Special Report:The use of proton pump inhibitors in acid-peptic Disorders 1999
2. Williams MP et al,Aliment Pharmacol Ther 1998 Nov;12(11):1079-89
8383 Dr Anshu P Gokarn
Higher rate of healing
Higher healing rates as compared to
omeprazole
Significantly greater improvement in
daytime pain.
Dekkers CP, Beker JA, Thjodleifsson B, Gabryelewicz A, Bell NE, Humphries TJ. Ignatius Hospital, Breda, the Netherlands.Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. Aliment Pharmacol Ther 1999 Feb;13(2):179-86
8484 Dr Anshu P Gokarn
Cloud ML et al,Dig.Dis.Sci.1998;43;993-1000
9384 85
120
20
40
60
80
100
% h
ea
lin
g r
ate
s
Rabeprazole
10 mg
Rabeprazole
20 mg
Rabeprazole
40 mg
Placebo
Healing Rates of Ulcerative GERD with different
doses of rabeprazole compared to placebo
8585 Dr Anshu P Gokarn
Rabeprazole Vs Omeprazole
in healing of Duodenal ulcer
69 62
98 93
0
20
40
60
80
100
% H
EA
LIN
G
After 2 weeks After 4 Weeks
Rabeprazole 20 mg Omeprazole 20 mg
Dekkers CPM,et al, comparison of rabeprazole 20mg vs omeprazole 20mg in the treatment of active duodenal ulcer,Aliment Pharmacol Ther.1999;13;179-86
8686 Dr Anshu P Gokarn
Rabeprazole Vs Ranitidine
in management of active duodenal ulcer disease
0
10
20
30
40
50
60
70
80
90
%
Healing Rates Complete resolution
of pain
Night time pain
severity
improvement in
overall well being
Rabeprazole 20 mg OD Ranitidine 150 mg D
Breiter JR et al. Am J Gastroenterol 2000 Apr; 95(4): 936-42
8787 Dr Anshu P Gokarn
Improvement in symptoms of
gastric ulcer
Dekkers CP et al. Aliment Pharmacol Ther 1999 Jan; 13: 49-57
69 61
98 93
84
68
0
20
40
60
80
100
% s
ym
pto
m r
eli
ef
Day pain After 2
weeks
Day pain after 4
weeks
Night pain after
4 weeks
Rabeprazole 20 mg Omeprazole 20 mg
8888 Dr Anshu P Gokarn
Intrinsic Anti H. pylori activity
Highly effective inhibitor of gastric acid
secretion in subjects infected with H. pylori.
Ohara T, Goshi S, Taneike I, Tamura Y, Zhang HM, Yamamoto T..Inhibitory action of a novel proton pump inhibitor, rabeprazole, and its thioether derivative against the growth and motility of clarithromycin-resistant Helicobacter pylori. Helicobacter 2001 Jun;6(2):125-9
Irreversibly inhibits urease enzyme produced by
H. pylori
Thus exerts a potent antibacterial activity
Inhibits Urease enzyme
9090 Dr Anshu P Gokarn
Thioether derivative of Rabeprazole has the
strongest inhibitory action against both the
growth and motility of CRPH
1. Park JB, Imamura L, Kobashi K, Kinetic studies of H. pylori urease inhibition by a novel PPI, Rabeprazole, Biol
Pharm Bull 1996 Feb;19:182-7
Potential novel agent for
Clarithromycin resistant H. pylori
(CRPH) eradication.
9191 Dr Anshu P Gokarn
4-day triple therapy in combination with
clarithromycin and amoxicillin - highly effective
Well tolerated in patients with gastric and
duodenal ulcer disease.
Eradication rate- 90%
Comparable with the established 7-day triple
therapy regimens.
Luth S, Teyssen S, Kolbel CB, Singer MV. Department of Medicine IV Gastroenterology/Hepatology), University Hospital of Heidelberg at Mannheim.4-day triple therapy with rabeprazole, amoxicillin and clarithromycin in the eradication of Helicobacter pylori in patients with peptic ulcer disease--A pilot study. Z Gastroenterol 2001 Apr;39(4):279-81, 284-5
Triple therapy for eradicating H.pylori
9292 Dr Anshu P Gokarn
1. Rapid onset of H+K+ATPase inhibition than
omeprazole,
2. Greater effect on intragastric pH after the
first dose1.
3. More potent inhibitor of proton pump than
omeprazole2.
Rabeprazole vs. Omeprazole
1. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
2. Langtray HD, Markham A. Rabeprazole:A review of its use in Acid related gastrointestinal
disorders, Drugs 199;58(4):725-742
9494 Dr Anshu P Gokarn
Rabeprazole vs. Omeprazole
3. More consistent symptom relief
4. Faster rate of healing
5. Lower potential for interaction with
cytochrome P450 enzyme system- Lesser
drug interactions
• Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
• Humphries TJ, Spera AC, Laurent L, Spanyers SA. Rabeprazole sodium (E3810) 20 mg daily does not affect the
pharmacokinetics of Phenytoin sodium in normal volunteers, AM J Gastroenterol 1996;91:1914
9595 Dr Anshu P Gokarn
Rabeprazole vs. Omeprazole
contd.
6. Two to ten fold greater antisecretory
activity.1
7. Significantly increases the production of
gastric mucin2.
1. Prakash A., Faulds. D .Rabeprazle, Drugs 1998 Feb; 55 (2),28,260-6
2. Takiuchi H, Asada S, Umegaki E et al. Effects of proton pump inhibitors, omeprazole,
lansoprazole and E-3810, on th egastrin mucin. 10th World Congress of
Gastroenterology; 1994 Oct
96 Dr Anshu P GokarnDr Anshu P Gokarn
8. Irreversibly inhibits the enzyme
urease produced by H. pylori
9. Potent anti-H.pylori activity
Rabeprazole vs. Omeprazole
contd.
1. Bell NE, Humpries TJ, Comparision of fasting gastric levels in 634 patients treated with either rabeprazole 20 mg or omeprazole 20mg once daily in 3 double blind therapeutic trials, Gasteroenterology 197;112(4) Suppl:A 70
2. Park JB, Imamura L, Kobashi K, Kinetic studies of H. pylori urease inhibition by a novel PPI, Rabeprazole, Biol Pharm Bull 1996 Feb;19:182-7
Dr Anshu P Gokarn 9797
Rabeprazole vs. Esomeprazole
Esomeprazole 40 mg results in 10%-15% higher
healing rates in GERD patients, compared to 20 mg
omeprazole racemate.
Same difference is found when the 20 & 40 mg
omeprazole racemate are compared to each other.
The chiral PPI prodrug is converted by acid into an
achiral cyclic sulfenamide which only then reacts with
the proton pump.
Therefore no pharmacodynamic argument in favour of
any single enantiomer formulation of any PPI. Kromer W. Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact of chirality. Scand J Gastroenterol Suppl 2001;(234):3-9
9898 Dr Anshu P Gokarn
Rabeprazole vs.
Esomeprazole
Lower incidences of Drug-Drug
interactions
Faster rate of H+K+ATPase inhibition
9999 Dr Anshu P Gokarn
Rabeprazole Vs Lansoprazole
Comparable Ulcer healing rates with
Lansoprazole 30 mg
Lower potential for drug interactions
Earlier and better symptom relief
American Pharmaceutical Assoc.,Special Report:The use of proton pump inhibitors in acid-peptic
Disorders 1999
100100 Dr Anshu P Gokarn
Cure Rates of H.pylori infection with
Lansoprazole and Rabeprazole
82.7
85.6
87
808182838485868788
Cure rates
Perc
ent cure
rate
s
LAC
RAC
R1/2AC
Miwa H et al,Efficacy of reduced dosage of rabeprazole in PPI/AC therapy for Helicobacter pylori infection: comparison of 20
and 40 mg rabeprazole with 60 mg lansoprazole.Dig Dis Sci 2000 Jan;45(1):77-82
Key: LAC: Lansoprazole 30mg bid with amoxicillin and clarithromycin
RAC:Rabeprazole 20mg bid with amoxicillin and clarithromycin
R1/2AC:10mg bid with amoxicillin and clarithromycin
Dr Anshu P Gokarn 101101
Safety profile
Similar short term side effect profile to
other PPIs
Safe for long-term use.
Serious side effects rare
Welage SL,Journal of the American Pharmaceutical association 1999:40:1
103103 Dr Anshu P Gokarn
Well tolerated
Very well tolerated as compared to
omeprazole and H2-receptor
antagonists.
No dose adjustments required for
special populations
Thjodleifsson and Cockburn,Alimentary Pharmacology & Therapeutic 1999 ; 13 s5 ; 17
104104 Dr Anshu P Gokarn
Dosage and administration
Adults:
Usual dosage: 20mg/day
Route of administration: Oral
Frequency of administration: Once daily
For GERD
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
105105 Dr Anshu P Gokarn
For pathological hyper secretory
conditions including Zollinger-Ellison
syndrome Adults:
Usual Dosage: 60mg/day
(Dosage should be adjusted based on clinical
response and should be continued as clinically
indicated. Doses up to 100 qd or 60 mg bid have
been administered).
Duration of therapy: some patients with
Zollinger-Ellison Syndrome have been treated
continuously for up to one year.
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
106106 Dr Anshu P Gokarn
Maximum dosage limits
Adults:
GERD, Duodenal ulcer, Gastric ulcer: 40 mg qd
Zollinger-Ellison Syndrome: 120mg qd
Elderly:
GERD, Duodenal ulcer, Gastric ulcer:40 mg qd
Zollinger-Ellison Syndrome: 120mg qd
Adolescents and Children:
Safe and effective use has not been established.
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
107107 Dr Anshu P Gokarn
Hepatic impairment No dosage adjustment required
Renal impairment No dosage adjustment is necessary
Intermittent haemodialysis
Extensively protein bound Not readily haemodialysable
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
108108 Dr Anshu P Gokarn
Maximum dosage limits
Overdose
No experience to date with
deliberate overdose.
Dosages of up to
120mg/day have been well
tolerated.
Product details, Pariet , Eisai, http://www.eisai.co.uk/pariet.htm
109109 Dr Anshu P Gokarn
Contraindications
Known hypersensitivity to rabeprazole,
other substituted benzimidazoles
(e.g.,lansoprazole, omeprazole)
110110 Dr Anshu P Gokarn
Gastric cancer
Hepatic disease
Children
Elderly
Japanese (AUC values were seen to be
50-60% greater)
Precautions
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
111111 Dr Anshu P Gokarn
Pregnancy
No data is available in human
pregnancy.
Studies in rats and rabbits have revealed
no evidence of impaired fertility or harm
to the foetus
Contraindicated during pregnancy.
112112 Dr Anshu P Gokarn
Lactation
It is not known whether rabeprazole sodium
is excreted in human breast milk.
No studies in lactating women have been
performed.
Excreted in rat mammary secretions.
Should not be used during breast feeding.
113113 Dr Anshu P Gokarn
Low potential for drug
interactions
Not complicated by clinically significant drug-
drug interactions with medications
metabolized by CYP 2C19
Humphries TJ, Spera AC, Laurent L, Spanyers SA. Rabeprazole sodium (E3810) 20 mg daily does not affect the pharmacokinetics of
Phenytoin sodium in normal volunteers, AM J Gastroenterol 1996;91:1914
114114 Dr Anshu P Gokarn
Drug interactions
Cyclosporine: metabolism is inhibited
Digoxin: AUC and Cmax is increased
Warfarin: No interaction
Antacids: Not clinically significant
Theophylline: No interaction
Diazepam: No interaction
Rabeprazole, Clinical Pharmacology 2000, Customised monograph
115115 Dr Anshu P Gokarn
Salient Features
Rapid onset of action
Higher rate of healing
Consistent Symptomatic relief
Increases gastric mucin, Heals mucosa
No effect on Steroidogenesis or endocrine functions
116116 Dr Anshu P Gokarn
Salient Features
The conformation of pump not altered as done by
Omeprazole.
Brings acid production level back to normal baseline
within 2 days as compared to 4 days with Omeprazole
Intrinsic anti H.pylori action
Low potential for drug interactions
Prevents stress induced increase in gastric mucosal
peptide – leukotriene content without altering mucosal
prostaglandin level.
117117 Dr Anshu P Gokarn
How my talk is structured
1. Physiology of Gastric acid secretion
2. Overview of Gastric Acid-Related
Disorders
3. Gastroesophageal Reflux Disease
4. Drugs used in GERD – protein pump
inhibitors
5. Rabeprazol
118118 Dr Anshu P Gokarn
Concluding Remarks
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