Gastroesophageal Reflux Disease(GERD)

Albertus R. Tjawan

What Is Gastroesophageal Reflux?

Gastroesophageal refers to the stomach and esophagus. Reflux means to flow back or return. Therefore, gastroesophageal reflux is the return of the stomach's contents back up into the esophagus

Definition
Digestive disorder that affects the lower esophageal sphincter (LES), the ring of muscle between the esophagus and stomach.

Classical Symptoms
Burning, pressure or pain Bitter or acid taste in the mouth Heartburn worsen after meal Heartburn is not linked to exercise or improve with rest. Dysphagia (difficult swallowing) Odynophagia (painfull swallowing)

Atypical Symptoms
Breathing problems such as asthma, cough, or wheezing Aspiration Pneumonia Interstitial fibrosis Laryngittis Globus Earache

Symptom Heartburn Regurgitation

Predominance (%) 80 54

Abdominal Pain
Cough

29
27

Dysphagia for solids

Hoarseness Belching Aspiration Wheezing Globus

23
21 15 14 7 4

What Other Factors Contribute to GERD?

Dietary and lifestyle choices may contribute to GERD. Certain foods and beverages, including chocolate, peppermint, fried or fatty foods, coffee, or alcoholic beverages, may trigger reflux and heartburn. Studies show that cigarette smoking relaxes the LES. Obesity and pregnancy can also play a role in GERD symptoms.

GERD, pathophysiology Lower esophageal sphinctor LES Gastric Emptying Time GET Esophageal clearance Protective esophageal mucosal layer H. pylori

The pathophysiology of reflux disease is multifactorial

Gastroduodenal factors :
Acid and pepsin

Duodenal agents Gastric emptying Helicobacter pylori Gastroesophageal junction factors :

Transient lower esophageal sphincter

relaxation Hypotensive lower esophageal sphincters Hiatal hernia Esophageal factors :

Esophageal clearance

Genetic factors

Pathophysiology of GERD
salivary HCO3

Impaired mucosal defence

oesophageal clearance of acid (lying flat, alcohol, coffee) Hiatus hernia

Impaired LOS (smoking, fat, alcohol) transient LOS relaxations basal tone
Bile and pancreatic enzymes

Pepsin

H+

acid output (smoking, coffee)

intragastric pressure (obesity, lying flat)

bile reflux

gastric emptying (fat)

de Caestecker, BMJ 2001; 323:7369. Johanson, Am J Med 2000; 108(Suppl 4A): S99103.

GERD, diagnosis Symptoms Endoscopy 24 hours intraesophageal pH monitoring H. pylori test

GERD, Complications Symptoms causes discomfort Slow blood loss which cause anemia Esophageal stricture Ulceration, bleeding, perforation Laryngitis and aspiration Barretts esophagus Esophageal adenocarcinoma

Differential diagnosis of GERD

Hiatus hernia
Esophageal stricture Esophageal cancer Chest pain of cardiac origin Functional dyspepsia

Nathoo, Int J Clin Pract 2001; 55: 4659.

Alarm features for GERD

Odynophagia

Dysphagia Alarm features

Bleeding

Vomiting

Weight loss

Nathoo, Int J Clin Pract 2001; 55: 4659.

Treatment scheme Step up approach Step down approach Continuous PPIs

Surgery Only in refractory cases

ALGORITME TATA LAKSANA GERD PADA PELAYANAN KESEHATAN LINI PERTAMA

GEJALA KHAS GERD

Gejala alarm Umur > 40 th

Tanpa gejala alarm

Terapi empirik Tes PPI

Respon menetap
Endoskopi

Respon baik

Terapi min-4 minggu

kambuh

Konsensus Gerd ,2004

On demand therapy

GERD treatment options

Lifestyle modifications

Antacids and alginates

PPIs

Approaches

H2RAs

Prokinetic motility agents

Hatlebakk & Berstad, Clin Pharmacokinet 1996; 31: 386406.

Lifestyle modifications for the management of GERD

Reduce weight Stop smoking Elevate head of bed

Modifications Avoid reflux-promoting agents (e.g. alcohol, coffee, some foods) (not evidence based) Eat small meals, no late meals, reduce fat

Goals of therapy Relieve symptoms Heal esophagitis Maintain patient in symptom free status Prevent complication Provide cost effective management

Comparison of acid control between PPIs

Intragastric pH with high-dose iv PPI therapy

Clinical pharmacology studies
H. pylori-negative healthy volunteers 24 hour iv infusion
n Median/mean 24-hour pH 5.8 5.0 Time pH>6 (024 hours) 12.6 5.56.7

Esomeprazole 80 mg + 8 mg/hour1
Pantoprazole 80 mg + 8 mg/hour2
* This is not a head to head study

25 36

1Rhss

K, et al. Intl J Clin Pharm Ther 2007;45:34554; 2Metz DC, et al. Aliment Pharmacol Ther 2006;23:98595

Comparison of PPI oral efficacy at pH > 4

Day 5 data, 5-way crossover study in patients with GERD
esomeprazole, 40 mg once daily rabeprazole, 20 mg once daily omeprazole, 20 mg once daily lansoprazole, 30 mg once daily

***

n=34 ***p<0.001 versus rabeprazole p<0.0001 versus lansoprazole, omeprazole and pantoprazole 0 5 10 15 Time intragastric pH>4 (hours) 20

pantoprazole, 40 mg once daily

Miner P, et al Am J Gastroenterol 2003;98:261620; Am J Gastroenterol 2006;101:404 - 406

Oral esomeprazole provides more effective acid control than pantoprazole iv

10.4

***

Day 1
6.0

esomeprazole oral, 40 mg once daily pantoprazole iv, 40 mg once daily

n=29 14.2

***

***p<0.001

Day 5
8.1

6 12 18 Time intragastric pH>4 (hours)

24

Armstrong D, et al. Aliment Pharmacol Ther 2003;18:70511

H+

H+ H+

H+ H+

H+

H+ H+ H+ H+

Proton pump

Proton pump

PPI

Parietal cell
H2 Receptor

Parietal Canalicular space cell

H2 Receptor

Histamin
H2 Blocker

Histamin

pH > 4 memegang peranan penting dalam

aktivitas pepsin
Aktivitas maksimum pepsin (%)

100

80
60 40 20 0 1 2 3 4 pH asam lambung

Berstad A. Scand J Gastroenterol 1970;5:343-8

Pengontrolan asam lambung antar PPI berbeda

Esomeprazole terbukti lebih efektif dalam mempertahankan pH > 4 vs PPI lainnya

Data hari ke-5, penelitian five-way crossover pada pasien GERD

Esomeprazole 40 mg sekali sehari rabeprazole 20 mg sekali sehari omeprazole 20 mg sekali sehari 13,3

15,3 ***

12,9

n=34 *** p=0,0004 vs rabeprazole; p<0,0001 vs lansoprazole, omeprazole dan pantoprazole

lansoprazole 30 mg sekali sehari

pantoprazole 40 mg sekali sehari 0 5 10

12,7

11,2 15 20

Lama pH lambung >4 (jam) Miner P et al. Am J Gastroenterol 2006;101:404406

Esomeprazole iv lebih efektif dalam mengontrol total asam yang dikeluarkan vs omeprazole iv
a) Basal acid output
Mean BAO (mmol/jam) 6 5

b) Pentagastrin-stimulated peak acid output

Mean PAO (mmol/jam) 40 35

esomeprazole iv, 40 mg omeprazole iv, 40 mg

n=23 **p<0,01

30
4 3 2
4,4

33,9

25 20 15

***p<0,001

**
20,0 15,7

**
1
0,7 1,5 1,0 1,0

10
5 0
Baseline
5,4

***
9,5

Baseline

34 hours

2324 Jam

35,5 Jam

2325,5 Jam

Waktu pada saat pemberian sediaan iv

Waktu pada saat pemberian sediaan iv

Keating GM, Figgitt DP. Intravenous Esomeprazole. Drugs 2004;64(8):875-882

Esomeprazole iv terbukti lebih cepat mencapai pH > 4 dibandingkan pantoprazole iv

Median pH 7 Hari I 6
Pantoprazole iv,

Esomeprazole iv, 40 mg infus sekali sehari

5 4
3 2 1

40 mg infus sekali sehari baseline

0
0 1 2 3 Waktu setelah pemberian (jam) 4

Wilder Smith et al. Aliment Pharmacol Ther 2004;20:1099-1104

Esomeprazole terbukti mempertahankan pH > 4 lebih lama dibandingkan pantoprazole iv

Median pH 7 6
Esomeprazole iv, 40 mg infus sekali sehari

Hari ke-5
Pantoprazole iv, 40 mg infus sekali sehari baseline

5
4 3 2 1 0 0 1 2 3 Waktu setelah pemberian (jam) 4

Wilder Smith et al. Aliment Pharmacol Ther 2004;20:1099-1104

Esomeprazole iv lebih efektif dalam mencapai target pengobatan vs pantoprazole iv

pH >6

5,1 5.1

**

Esomeprazole iv, 40mg infus satu kali sehari Pantoprazole iv, 40mg infus satu kali sehari

11

pH >5

8,6 8.6 2,9 2.9

*
n = 21 Pada pasien H.pylori negatif *p < 0,0001

pH > 4

11,8 11.8 5,6 5.6

**p < 0,001

Lama pengontrolan asam lambung (jam)

Hartmann D et al. European Journal of Gastroenterology & Hepatology 2007, 19:133-137

Esomeprazole oral terbukti lebih efektif dibandingkan pantoprazole iv dalam mempertahankan pH > 4
esomeprazole oral 40 mg sekali sehari

10,4

***

pantoprazole iv, 40 mg sekali sehari

Hari 1
6,0

n=29 *** p<0,001

14,2

***

Hari 5
8,1

6 12 18 Lama mempertahankan pH intragastrik >4 (jam)

24

Armstrong et al .Aliment Pharmacol Ther 2003; 18: 705711.