The ROLE OF PPI IN THE

MANAGEMENT of

GERD
Wizhar Syamsuri

Division of Internal Medicine

Putra Bahagia Hospital

Apa yang dimaksud

GastroEsophageal Reflux Disease ?
GERD adalah suatu
keadaan dimana isi
lambung /duodenum
bergerak berbalik arah
masuk ke esophagus
(reflux) dan
menimbulkan keluhan.

Physiologic vs Pathologic
Physiologic GERD

Postprandial
Short lived
Asymptomatic
No nocturnal sx

Pathologic GERD

Symptoms
Mucosal injury
Nocturnal sx

The overall definition of GERD and

its constituent syndromes (Figure 2)

Vakil N et al. Am J Gastroenterol 2006; 101: 1900 - 1920

Incidence
It is one of the most common conditions
affecting the gastrointestinal system.
Anywhere from 36-77% of people have symptoms of
GERD (heartburn, regurgitation of acid etc.) spread
equally between men and women.

7% have daily heartburn

14-20% have weekly heartburn
15-50% have monthly heartburn

Epidemiology GERD

J Dent, H B El-Serag, M-A Wallander and S Johansson 2005;54;710-717 Gut ; a systematic review Epidemiology of gastro-oesophageal reflux disease

Mechanisms of GERD (3)

Intrinsic Mucosal Abnormalities
Abnormal esophageal gland secretion
Impaired mucosal resistance

Defective Antireflux Barrier

LES Hypotension/incompetence
Increased Transient Relaxation
Hiatal Hernia

Ineffective Esophageal Clearance

Defective motility
Defects in saliva
Recumbency

Delayed Gastric Emptying

Symptoms of Classic GERD

Heartburn (pyrosis)
Most common clinical manifestation
Burning, tight sensation felt beneath the lower sub sternum
and spreads upward to throat or jaw
Felt intermittently
Aggravated by change in position
Promt relief by antacids
Relieved by milk, alkaline substances, or water

Regurgitation
Effortless return of food or gastric contents
from stomach into esophagus or mouth
Described as hot, bitter, or sour liquid coming
into the mouth or throat

Gastric symptoms such as

Early satiety, postmeal bloating, nausea, and
vomiting
Related to delayed gastric emptying

Symptoms typically occur after eating a meal

and
can be especially noticeable with a large meal or
spicy foods.

Symptoms may be relieved by antacids.

Symptoms often are worse
when lying flat, straining or sleeping.
Symptoms made worse
Fatty foods, chocolate, coffee, peppermint as well as alcohol
and use of tobacco products can cause or worsen
symptoms.
Theophylline, Albuterol, and Calcium channel blockers can
also cause symptoms of GERD.

The GERD symptom pattern is similar in

patients with and without esophagitis
Heartburn
(100%)

Epigastric pain

Regurgitation

Nausea

Belching

Bloating

Scale=% of patients with symptom

without
esophagitis
with esophagitis

Abdominal pain

Carlsson et al 1998b

Complications of GERD
Erosive/ulcerative esophagitis
Esophageal (peptic) stricture
Barretts esophagus
Adenocarcinoma

Endoscopic Spectrum of GERD

Normal
40-50%

Esophagitis
30-50%

Stricture
10 - 20%

Barretts Esophagus
10 - 20%

Peptic Stricture
Barium Swallow

Endoscopy

Diagnostic Studies
History and PE
Barium swallow

Can detect protrusion of gastric fundus

Upper GI endoscopy

Useful in assessing LES competence

Degree of inflammation, scarring, strictures
Biopsy and cytologic specimens
Differentiate carcinoma from Barretts esophagus

Esophageal manometric (motility) studies

Measure pressure in esophagus and LES

Monitoring pH

Laboratory or 24-hour ambulatory

Determine esophageal pH using specially designed
probes

High-dose proton pump inhibitor treatment

for 2 weeks can be used as a first step in
diagnosis of GERD ( EMPIRIC THERAPY )
Radionuclide tests

Detect reflux of gastric contents

Rate of esophageal clearance

Endoscopy
Indications for endoscopy
Alarm symptoms
Dysphagia
Early satiety
GI bleeding
Odynophagia
Vomiting
Weight loss
Iron deficiency anemia

Empiric therapy failure

Preoperative evaluation
Detection of Barretts esophagus

Upper endoscopy
Most commonly used
test to evaluate the
esophagus and
stomach.
Requires mild sedation
Requires technical skill
and experience
Most accurate way to
evaluate damage to or
inflammation of the
upper gastrointestinal
tract.

Tipe GERD
Patients with GERD
100%
Patients with NERD
60%

Patients with esophagitis

40%

Patients without
complications
35%

Patients with
complications
5%
Adapted from Quigley 2001

NERD
Didefinisikan dengan adanya gejalagejala umum, termasuk didalamnya
heartburn ,regurgitasi , nyeri dada dan
gejala extra-esophageal seperti ;
batuk,serak,asthma,yang disebabkan
reflux dari lambung/usus dan tidak ada
kerusakan jaringan pada pemeriksaan
upper endoscopy.

Tabel 1. Klasifikasi Los Angles

Derajat
kerusakan

Gambaran Endoskopi

Erosi kecil-kecil pada mukosa esofagus

dengan diameter < 5 mm

Erosi pada mukosa/lipatan mukosa dengan

diameter > 5mm tanpa saling berhubungan

Lesi yang konfluen tetapi mengenai/

mengelilingi seluruh lumen

Lesi mukosa esofagus yang bersifat

sirkumferensial (mengelilingi seluruh lumen
esofagus)

The LA Classification system for the

endoscopic assessment of reflux
esophagitis
Grade A

Grade B
One (or more)
mucosal break, no
longer than 5 mm,
that does not extend
between the tops of
two mucosal folds

Grade C

One (or more) mucosal

break, more than 5 mm
long, that does not
extend between the tops
of two mucosal folds

Grade D
One (or more)
mucosal break
that is continuous
between the tops
of two or more
mucosal folds,
but which involves
less than 75% of
the circumference

One (or more) mucosal

break that involves at
least 75% of the
esophageal circumference

Lundell et al 1999

A.
B.
C.
D.
E.

Esofagus normal
Esofagitis ringan
Esofagitis sedang
Esofagitis berat
Esofagus Barret

Treatment of GERD
(Collaborate Cares)
Goal of Treatment
Eliminate symptoms
Heal esophagitis
Manage or prevent complications
Maintain remission

Lifestyle modifications (1)

Corner stone of GERD therapy
Avoid factors that cause reflux

Stop smoking
Avoid alcohol and caffeine
Avoid acidic foods

Modify diet

Eat more frequent but smaller meals

Avoid fatty/fried food, peppermint,
chocolate, alcohol,
carbonated beverages, coffee and tea

Stress reduction techniques

Weight reduction, if appropriate
Small frequent meals
Elevate HoB 30o (4-6 inches)
Do not lie down for 2 to 3 hours after
eating
Avoid late-night eating (2-3 hs of bedtime)
Evaluate effectiveness of medications
Observe for side effects of medications

Drug Therapy (2)

Two approaches
1.

Step up

2.

Start with antacids and OTC H2R blockers and progress to

prescription H2R blockers and finally PPIs

Step down

Start with PPI and titrate down to prescription H2R blockers

and finally OTC H2R blockers and antacids

Step-up
Approaches

Step-down
Approaches

PPI ( standard dose )

H2RA ( standar dose )
H2RA ( anti-reflux dose )

Proton pump inhibitors (PPI)

Decrease gastric HCl acid secretion
Promote esophageal healing in 80% to 90% of
patients
May be beneficial in esophageal strictures
Headache: Most common side effect

Treatment
H2RAs vs PPIs
12 week freedom from symptoms
48% vs 77%

12 week healing rate

52% vs 84%

Speed of healing
6%/wk vs 12%/wk

Proton Pump Inhibitors

omeprazole, lansoprazole, pantoprazole, rabeprazole
(Pariet), esomeprazole (Nexium).
Symptom relief in 90%

Healing 80-90%
Maintenance of remission 70-95%

Equally effective in >90% of individuals

Long term safety issues resolved
More cost effective than H2RAs in complicated or
moderate to severe disease

Maintenance Therapy for GERD

For patients with complicated disease
25-40% maintained in remission with H2RAs vs. 80-90%
with PPIs
40-50% of patients require PPIs for maintenance of
remission
The lowest effective dose is therapeutic goal
Cost effectiveness is determined by efficacy not price of
drug

Effectiveness of Medical
Therapies for GERD
Treatment

Response

Lifestyle modifications/antacids

20 %

H2-receptor antagonists

50 %

Single-dose PPI

80 %

Increased-dose PPI

up to 100 %

% esophagitis cases healed

PPIs are the most effective drugs

for the initial treatment of GERD
100
PPIs
80
60

H2RAs

40

Placebo

20
0

4
6
8
Weeks of treatment

10

12

Chiba et al. Gastroenterology 1997

p < 0.0005

Surgical Therapy
Surgical therapy

Reduce reflux of gastric contents by enhancing integrity of LES

Most performed laparoscopically

Surgical therapy
Necessary if

Conservative therapy fails

Hiatal hernia present
Esophageal stricture and stenosis
Chronic esophagitis
Bleeding

Surgical therapy

Fundus of stomach is wrapped around lower portion of

esophagus
Reinforce and repair defective barrier

Example: Nissen fundoplication

Tabel 2. Efektivitas Terapi Obat-obatan

Golongan
Obat

Mengurangi
Gejala

Penyembuhan
Lesi Esofagitis

Mencegah
Komplikasi

Mencegah
Kekambuhan

Antasid

+1

Prokinetik

+2

+1

+1

Antagonis
reseptor H2

+2

+2

+1

+1

Antagonis
reseptor H2+
prokinetik

+3

+3

+1

+1

Antagonis
reseptor H2
dosis tinggi

+3

+3

+2

+2

Penghambat
pompa proton

+4

+4

+3

+4

Pembedahan

+4

+4

+3

+4

Treatment Modifications for

Persistent Symptoms
Improve compliance
Optimize pharmacokinetics
Adjust timing of medication to 15 30 minutes
before meals (as opposed to bedtime)
Allows for high blood level to interact with
parietal cell proton pump activated by the meal

Consider switching to a different PPI

AGA TR & MPS on Management of

GERD*
1.

2.
3.
4.
5.

Antisecretory drugs for the treatment of patients with esophageal GERD syndromes
(healing esophagitis, symptomatic relief & maintaining healing of esophagitis). In
these uses, PPIs are more effective than H2RAs, which are more effective than
placebo
Long-term use of PPIs for the treatment of patients with esophagitis once they have
proven clinically effective. Long-term therapy should be titrated down to the lowest
effective dose based on symptom control
When antireflux surgery & PPI therapy are judged to offer similar effectiveness in a
patient with an esophageal GERD syndrome, PPI therapy should be recommended
as initial therapy because of superior safety
When a patient with an esophageal GERD syndrome is responsive to, but
intolerant of, acid suppressive therapy, antireflux surgery should be recommended
as an alternative
Twice-daily PPI therapy as an empirical trial for patients with suspected reflux chest
pain syndrome after a cardiac etiology has been carefully considered

* U.S. Preventive Services Task Force Grades - Grade A recommendations (strongly recommended based on good evidence that it improves
important health outcomes)
AGA American Gastroenterological Association, TR Technical Review, MPS Medical Position Statement, PPIs Proton Pump Inhibitors, H2RAs Histamine Receptor Antagonists

Kahrilas PJ et al. Gastroenterology 2008; 135: 1383 - 1391

Terapi Empiris
Dinamakan juga PPI test
Dosis ganda PPI
1-2 minggu
Positif; bila keluhan hilang 75%
dalam 1 minggu

Konsensus GERD PGI, 2004

Treatment option in GERD

Continuous
Maintenance
(month- year)
Intermittent
Courses
S

(weeks)

On-demand
(days)
S

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

S
S : symptom recurrence

An Algorithm Approach
On-Demand strategy not appropriate for all
GERD patients.
Algorithm needed to specify:
* Initial evaluation
* Treatment protocols
* Follow-up protocols

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

Endoscopy not required

PPI standard dose

2 4 weeks
Failure
Endoscopy

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

Success
PPI on demand

Endoscopy
NERD

Mild erosive
esofagitis

Severe erosive
esofagitis
PPI
4 8 weeks
Success:
Continuous PPI

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

Endoscopy
NERD

Mild erosive
esofagitis

PPI
4 8 weeks
Success:
On Demand PPI

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

Severe erosive
esofagitis

Endoscopy
NERD

Mild erosive
esofagitis

Severe erosive
esofagitis

PPI
4 8 weeks
Success:
On Demand PPI

P. Bytzer* & A. L. Blum , Rationale and proposed algorithms for symptom-based proton pump
inhibitor therapy for gastro-oesophageal reflux disease Alimentary Pharmacology & Therapeutics,
Volume 20 Page 389 - August 2004

Failure:
Prolonged therapy

HARI 1 AKTIFASI PPI

3
6

1. Pantoflickova D, et al. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors.
Aliment Pharmacol Ther 2003; 17: 1507-1514
2.Kromer W et al. Differences in pH-Dependent Activation Rates of Substituted Benzimidazoles and Biological in
vitro Correlates.
Pharmacology 1998; 56: 57-70

HARI 1 CEPAT MENGENDALIKAN

ASAM

Pada

HARI 1

Secara nyata, Pariet 20mg lebih kuat dalam

menghambat sekresi asam dibanding PPI lainnya
(p0.03)

Hal ini dibuktikan dengan nilai

tengah pH 24 jam pertama
sebesar 3.4 pada kelompok yang
mendapatkan pengobatan dengan
Pariet 20mg dan secara nyata
lebih tinggi dibanding PPI lainnya
(p0.03)

Pantoflickova D, et al. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors.
Aliment Pharmacol Ther 2003; 17: 1507-1514

Dengan Pariet 20mg sekali sehari..

Pada

HARI
1

Keluhan heartburn BERAT dan SANGAT BERAT pada

pasien GERD diperbaiki, baik keluhan SIANG atau
MALAM hari.

A randomized, double blind & comparative study

4.7%

HARI 1 CEPAT BEBASKAN

KELUHAN PADA KASUS BERAT &
SANGAT BERAT

4.7%

Terbukti bahwa Pariet

20mg dosis standard
sekali sehari lebih
superior dibandingkan PPI
lain dengan dosis tinggi

Holtman G, et al. A randomized, double-blind, comparative study of standard-dose rabeprazole and highdose omeprazole in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2002; 16: 479-485

HARI 1 CEPAT BEBASKAN

KELUHAN SIANG & MALAM HARI

Dengan Pariet 20mg sekali sehari..

80%

pasien GERD mendapat perbaikan keluhan

heartburn SIANG dan MALAM hari pada HARI 1

Robinson M, et al. Onset of symptom relief with rabeprazole: a community-based, open-label

assessment of patients with erosive oesophagitis. Aliment Pharmacol Ther 2002; 16: 445-454

Jika dengan PPI lain sudah tidak efektif.

meskipun sudah ditingkatkan dosisnya..

HARI 1 CEPAT BEBASKAN

KELUHAN JIKA GAGAL DENGAN
PPI LAIN

Dengan Pariet 20mg sekali sehari..

Pada

HARI 1

pasien terbebas dari keluhan heartburn SIANG

dan MALAM hari
Sejumlah 502 dari 2579 pasien GERD
dilaporkan telah mendapatkan pengobatan
dengan Lansoprazole atau Omeprazole tetapi
gagal, meskipun dosisnya sudah ditingkatkan
menjadi dosis tinggi.
Dari 502 pasien tersebut mendapatkan
pengobatan dengan Pariet 20mg dengan dosis
sekali sehari menunjukkan:
Lebih dari 50% terbebas dari keluhan heartburn
pada hari 1
Dan pengobatan dilanjutkan samapai dengan
minggu ke 4, terbukti lebih dari 80% terbebas
dari keluhan.

Robinson M, et al. Onset of symptom relief with rabeprazole: a community-based, open-label

assessment of patients with erosive oesophagitis. Aliment Pharmacol Ther 2002; 16: 445-454

HARI 1 CEPAT MENGENDALIKAN

pH OPTIMAL

Pada

Secara nyata, Pariet 20mg sekali sehari

mempertahankan pH optimal >3 dan pH > 4
lebih lama dibandingkan Esomeprazole 40mg

HARI 1

Hal ini ditunjukkan dari persentase rata rata

lamanya mempertahankan pH >3 dan pH > 4
pada kelompok yang mendapatkan
pengobatan dengan Pariet 20mg sekali sehari
lebih tinggi secara nyata dibanding
Esomeprazole 40mg

Catatan:
pH optimal adalah pH ideal yang dibutuhkan untuk pengobatan penyakit akibat asam lambung
Ulkus : pH dipertahankan > 3
GERD : pH dipertahankan > 4

Warrington S, et al. Effects of single doses of rabeprazole 20mg and esomeprazole 40mg on 24-h
intragastric pH in healthy subjects. Eur J Pharmacol 2006; 62: 685-691

CEPAT SEMBUH

84%

pasien GERD derajat menunjukkan kesembuhan secara

endoskopis dengan pengobatan Pariet
III pada minggu ke 20mg sekali sehari

Dosis standard Pariet 20mg setara

dengan dosis tinggi Omeprazole 40
dalam menyembuhkan lesi

Holtman G, et al. A randomized, double-blind, comparative study of standard-dose rabeprazole and highdose omeprazole in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2002; 16: 479-485