This document provides information on Gastroesophageal Reflux Disease (GERD). It begins with definitions and descriptions of GERD and its typical and atypical symptoms. It then discusses the pathophysiology, impact on quality of life, classification (NERD, erosive esophagitis, Barrett's esophagus), and symptoms. Diagnostic testing options are presented including endoscopy, biopsies, and pH monitoring. Risk factors, prevalence worldwide, and limitations of current PPI therapies are reviewed. Finally, the document introduces Vonoprazan as a novel potassium-competitive acid blocker with advantages over PPIs such as longer half-life, rapid and sustained acid control demonstrated in clinical trials, and superior

1. Gastroesophageal Reflux Disease
DR.GR-RahiMoon
Resident Internal Medicine
Medical Unit#01
LIAQUATIAN Academic & Reseach Society(LARS)
An Old Disease with New
Approaches

2. Hypertension, untreated
Normal female
Angina pectoris
Duodenal ulcer, untreated
Psychiatric patients
110
Normal male
Heart failure (mild)
Esophagitis, untreated
PGWB Index score
GERD has a greater impact on quality
of life than other common diseases
60 70 80 90 100
Dimenas E. Scand J Gastroenterol 1993;28 Suppl 199:18.

3. What is GERD?
•GERD should be defined as symptoms or
complications resulting from the reflux of gastric
contents into the esophagus or beyond, into the
oral cavity (including larynx) or lung.

4. Clinical Presentation of GERD
Typical/
Esophageal
Heartburn
Acid regurgitation
Atypical/
Supraesophageal
Chest pain
Laryngitis
Asthma
Sinusitis
Chronic cough
Aspiration
pneumonia
Tooth decay

5. Pathophysiology of GERD
Impaired acid neutralization by
saliva and HCO3
Impaired esophageal
motility
Hiatal hernia
LES (inappropriate
relaxation)
Delayed gastric emptying/
gastroparesis
LES=lower esophageal sphincter

6. There is only weak evidence that lifestyle factors
aggravate GERD symptoms
• Obesity:
• severity of esophagitis correlates with weight only when
BMI >30 kg/m2
• contradictory studies into weight loss indicate no
effect/improvement in GERD.
• Smoking:
• lowers LES pressure and the acid-neutralising effect of
saliva.
• Physical activity:
• running might provoke GERD by increasing TLESRs.
Meining A et al. Am J Gastroentero 2000;95:2692.

7. Medications may aggravate
GERD symptoms
Impairment of LES function:
• beta-adrenergic agonists
• theophylline
• anticholinergics
• tricyclic antidepressants
• progesterone
• alpha-adrenergic antagonists
• diazepam
• calcium channel blockers.
Damage to the esophageal
mucosa:
• acetylsalicylic acid and other
NSAIDs
• tetracycline
• quinidine
• bisphosphates.

8. Cough
response
Stimulation of
vagus nerve
Gastric refluxate
Esophageal–bronchial
transmission via
cough center
Aspiration to lower
respiratory tree
Gastric refluxate
Cough and GERD:
2 Possible Mechanisms

9. Phenotypic Classification of GERD
GERD
NERD*
Erosive
Esophagitis
Barrett’s
Esophagus
Fass et al. Alim Pharm Ther 2005
*NERD: Non-Erosive Reflux Disease

10. What are the Symptoms of
Symptomatic GERD?
• Heartburn
• Regurgitation
• Chest pain
• Impaired QOL
• Others (burning mouth/tongue)
• Atypical (“supraesophageal”) symptoms
• These are the same symptoms as patients with erosive esophagitis
and Barrett’s esophagus
• The severity of these symptoms CANNOT PREDICT the subtype of
GERD into which a patient falls prior to endoscopic examination

11. Taken from Medscape.com

12. Endoscopic Images
Normal Squamo-
columnar junction
LA Grade A
Esophagitis
LA Grade D
Esophagitis

14. Esophageal stricture –
endoscopic appearance

15. Metaplasia of the esophagus:
Barrett’s esophagus
Definition: a change in the esophageal epithelium of
any length that can be recognised at endoscopy and
is confirmed to have intestinal metaplasia by biopsy
of the tubular esophagus and excludes intestinal
metaplasia of the cardia.
Squamous epithelium Columnar epithelium

16. Indications for additional investigations
• Atypical history.
• Symptoms are frequent and long-standing or do not respond to
therapy.
• Alarm symptoms are present:
• severe dysphagia
• weight loss
• bleeding
• hematemesis
• mass in the upper abdomen
• anemia

17. Why Do Therapies Fail to
Control Symptoms?

18. Reasons for treatment “Failure”
• Patient non-compliance
• Persistent esophageal acid exposure
• Hypersecretory state
• Large hiatal hernia
• Nocturnal acid breakthrough
• Acid-sensitive esophagus
• Non-acid reflux
• Wrong diagnosis
• Functional heartburn (NOT GERD!!)

19. Survey of Satisfaction Status with PPI’s
Patients dissatisfied
with PPI
Physicians
dissatisfied with PPI
Ref: Digestive Diseases and Sciences volume 55, pages3415-3422 (2010)
1000 patients & physicians survey in the US

20. Diagnosis GERD
• Upper endoscopy is not required in the presence of typical
GERD symptoms. Endoscopy is recommended in the presence of
alarm symptoms and for screening of patients at high risk for
complications.
• Repeat endoscopy is not indicated in patients without Barrett’s
esophagus in the absence of new symptoms. (Strong
recommendation, moderate level of evidence)
• Barium radiographs should not be performed to diagnose GERD
(Strong recommendation, high level of evidence).

21. Diagnosis GERD
• Routine biopsies from the distal esophagus are not
recommended specifically to diagnose GERD. (Strong
recommendation, moderate level of evidence).
• Esophageal manometry is recommended for preoperative
evaluation, but has no role in the diagnosis of GERD. (Strong
recommendation, low level of evidence).

22. Prevalence of GERD Worldwide

23. US
18.1% to 27.8%
Ref. https://www.ncbi.nlm.nih.gov/books/NBK441938/
EU
8.8% to 25.9%
Ref. World J Gastroenterology. 2017 Jan 21; 23(3): 525–532.
Prevalence of GERD Worldwide

24. Prevalence of GERD,Peptic Ulcer &
H. pylori infection in Pakistan
Ref. Journal of Pakistan Medical Association. Volume 42, Issue 9
Professional Medical Joiurnal. Vol 17 No 03 (2010): Vol. 17 No. 03
Disease Burden in
Pakistan
Pakistan spend nearly 27
Billion PKR annually for acid
related Diseases.
IMS data 2021
The age adjusted rate
of gastric ulcer patients
shows that 0.7 males and 0.3
females/10,000 population of
Karachi might be suffering
from gastric ulcer.
(Among PUD Patients)
Prevalence of infection
with H. pylori varied to
92% in Pakistani
population
In Pakistan 24% of the
population is suffering
from GERD
Ref. Journal of the College of Physicians
and Sureons--Pakistan: JCPSP 15(9):532-4

25. • Helicobacter pylori (H. pylori) infection is one
of the most common chronic bacterial infections
in humans affecting approximately 4.4 billion
people worldwide, with a prevalence of 28% to
84% in different populations
• Globally Peptic ulcer disease affects
approximately 4.6 million people annually.
Prevalence of H. pylori infection and Peptic
Ulcer Worldwide
Clinical—alimentary tract| volume 153, issue 2, p420-429, august 1, 2017
Peptic ulcer. OMICS International. August 1, 2019

26. Current Therapies Status

27. Current therapies including
PPIs, have limited response due
to:
1. Slow onset of action
2. Insufficient duration of acid control
Which results in..
Nocturnal
heartburn
Postprandial
heartburn
J.Neurogastroenterol Motil, Vol. 24 No. 3 July,
2018
Which can leads to..

28. Unmet Needs ,Limitations of PPI’s
Molecule % Time pH>4 a No. Hours pH>4 b Mean pH
Esomeprazole 58.43 % 14 hours 4.04
Rabeprazole 50.53 % 12.1 hours 3.70
Omeprazole 49.16 % 11.8 hours 3.54
Lansoprazole 47.98 % 11.5 hours 3.56
Pantoprazole 41.94 % 10.1 hours 3.33
Ref: Current Diagnosis & Treatment 2020 (Gastro)
3rd edition 2020
Chapter 11 ,Page 163 Table 11-5
a. Percentage of time that intragastric pH was 4.0
b. Mean 24-Hour intragastric pH on Day 5 by treatment group
PPI’s are unable to maintain pH>4

29. Reflux symptoms persist after 1st dose
Symptoms persist after 3 days
Heartburn & regurgitation not relieved
Patients used twice daily PPI
Addition of another antacid required with PPI
Unmet needs of Patients with PPI
treatments
66%
50%
40%
22%
42%
J.Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018

30. ReVolutionization
In The Management Of Acid Peptic Diseases

31. Mode of Action
Vonoprazan is a Potassium
Competitive Acid Blocker
(P-CAB) and Inhibits acid
secretion by Competitively
Blocking availability of
potassium to hydrogen-
potassium ATPase.
J.Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018

32. Advantages of P-CAB
VS
Activated drug (needs no
activation also stable in acid)
>7 hours half-life
No dependency on meal
J. Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018
Limitations of PPIs
Prodrug (need acid for activation
but active drug is unstable in acid)
<2 hours half-life
Meal required for activation
(one hour before meal recommended)
Comparison PPI V/S P-CAB

33. Indication and Uses
https://newdrugapprovals.org/2016/04/24/vonoprazan-fumarate/
• Gastro-oesophageal reflux/ reflux oesophagitis/
erosive oesophagitis
• Peptic ulcer /gastric ulcer/ duodenal ulcer
• Helicobacter pylori eradication

34. Clinical Evidences

35. Acid-inhibitory effects of Vonoprazan 20 mg compared with
esomeprazole 20 mg
Ref. Sakurai et al, Alimentary Pharmacology and Theraputics,2015
Method:
Randomised, open-label study, vonoprazan 20 mg and esomeprazole 20 mg (Study
V vs. E) were orally administered daily for 7 days.
Result:
• Acid-inhibitory effect (pH4 HTR) of vonoprazan was significantly greater than
that of esomeprazole on both Days 1 and 7; Day 7 difference in pH4 HTR for
vonoprazan vs. esomeprazole was 24.6%.
• The Day 1 to Day 7 ratio of 24-h pH4 HTRs was >0.8 for vonoprazan,
compared with 0.370 for esomeprazole.
pH above 4 maintenance Study

36. Rapid and Potent acid control
Ref. Sakurai et al, Alimentary Pharmacology and Theraputics,2015
pH above 4 maintenance Study

37. Vonoprazan versus lansoprazole for the initial relief of
heartburn in patients with Erosive oesophagitis
Ref. Oshima et al.AP&T 2018. Aliment Pharmacol Ther.2019;49:140-146
Methods:
Patients (n = 32) with erosive oesophagitis who experienced heartburn at least
once a week were randomised in a double-blind manner to receive either daily
vonoprazan (20 mg) or lansoprazole (30 mg) before breakfast for 14 days.
Results:
• Heartburn was relieved sooner with vonoprazan than with lansoprazole (P <
0.05).
• Heartburn was completely relieved in Vonoprazan (31.3%) than
lansoprazole (12.5%) of patients on day 1, respectively.
• Significantly more patients achieved complete nocturnal heartburn relief with
vonoprazan than lansoprazole (P < 0.01).
Vonoprazan efficacy in Nocturnal
Heart burn

38. Vonoprazan demonstrated a faster time to complete heart burn
relief than Lansoprazole, and this complete relief was most
pronounced for night time heart burn.
Ref. Oshima et al.AP&T 2018. Aliment Pharmacol Ther.2019;49:140-146
Better Heart burn relief with Vonoprazan Vs PPI
Vonoprazan efficacy in Nocturnal
Heart burn

39. Vonoprazan, a novel potassium competitive acid blocker,
vs. lansoprazole for the healing of Erosive oesophagitis
Ref. Ashida et al, Aliment Pharmacol ther 2016
Method:
In this multicentre, randomised, double-blind, parallel-group comparison study,
patients with endoscopically confirmed EE (LA Classification Grades A–D) were
randomly allocated to receive vonoprazan 20 mg or lansoprazole 30 mg once daily
after breakfast
Result
The proportion of patients with healed EE up to week 8 was 99.0% for vonoprazan
and 95.5% for lansoprazole, thus verifying the non-inferiority of vonoprazan (P <
0.0001).
Erosive Esophagitis Study

40. Superior healing rate in Erosive
Esophagitis
Ref. Ashida et al, Aliment Pharmacol ther 2016

41. Maintenance for healed erosive esophagitis: Phase-3
comparison of vonoprazan with lansoprazole
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Methods
•607 patients aged ≥ 20 years.
•All patients in whom endoscopic healing of EE was confirmed 2, 4, or 8 wk
after the start of the study medication were immediately stratified by
baseline endoscopic LA Classification grade (A/B or C/D).
•Subsequently randomized in a 1:1:1 ratio to receive maintenance therapy
with vonoprazan 10 mg (n = 202), vonoprazan 20 mg (n = 204), or
lansoprazole 15 mg (n = 201) given once daily after breakfast for 24 wk.
Maintenance Study

42. Minimal recurrence of Erosive
Esophagitis
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Lansoprazole 15mg

43. Results
• Rates of EE recurrence during the 24-wk maintenance period were 16.8%
(lansoprazole 15 mg), 5.1% (vonoprazan 20 mg), and 2.0%
(vonoprazan 10 mg), respectively. Vonoprazan was shown to be non-
inferior to lansoprazole 15 mg (P < 0.0001 for both doses).
• Recurrence rates in patients with baseline LA grade C/D EE were significantly
reduced with vonoprazan 10 mg (13.2%) and 20 mg (4.7%) vs
lansoprazole 15 mg (39.0%) (P = 0.0114 and P = 0.0001, respectively).
Conclusion
Vonoprazan was shown to be non-inferior to lansoprazole 15 mg at both
investigated doses.
Maintenance for healed erosive esophagitis: Phase-3
comparison of vonoprazan with lansoprazole
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Minimal recurrence of Erosive
Esophagitis

44. Vonoprazan, a novel potassium-competitive acid blocker,
as a component of 1st and 2nd line triple therapy for
Helicobacter pylori eradication
Ref. Murakami K, et al. Gut 2016;65:1439–1446. doi:10.1136/gutjnl-2015-311304
Method:
Randomised, double-blind, multicentre, parallel-group study
was conducted to verify the noninferiority of vonoprazan 20 mg
to lansoprazole 30 mg as part of first-line triple therapy (with
amoxicillin 750 mg and clarithromycin 200 or 400 mg) in H
pyloripositive patients with gastric or duodenal ulcer history.
Eradication of H. pylori infection

45. Better eradication of H. pylori
infection
Ref. Murakami K, et al. Gut 2016;65:1439–1446. doi:10.1136/gutjnl-2015-311304

46. Result:
• The first-line eradication rate (primary end point) was 92.6% with
vonoprazan versus 75.9% with lansoprazole, with the difference being
16.7% in favour of vonoprazan, thus confirming the non-inferiority of
vonoprazan (p<0.0001).
• The eradication rate was significantly higher with vonoprazan (82.0%)
compared with lansoprazole (40.0%) in those patients infected with CLR-
resistant strains (p<0.0001).
• The second-line eradication rate (secondary end point) was also high
(98.0%) in those who received second-line therapy (n=50).
Ref. Murakami K, et al. Gut 2016;65:1439–1446. doi:10.1136/gutjnl-2015-311304
Vonoprazan, a novel potassium-competitive acid blocker,
as a component of 1st and 2nd line triple therapy for
Helicobacter pylori eradication
Better eradication of H. pylori
infection

47. Vonoprazan, a novel potassium-competitive acid blocker,
as a component of 1st and 2nd line triple therapy for
Helicobacter pylori eradication
Ref. Murakami K, et al. Gut 2016;65:1439–1446. doi:10.1136/gutjnl-2015-311304
Conclusion
Vonoprazan is effective as part of first-line triple therapy and as
part of second-line triple therapy in H pylori-positive patients
with a history of gastric or duodenal ulcer.
Better eradication of H. pylori
infection

48. • Rapid Onset of action
• Potent Acid control
• Durable 24-Hr activity (Controls nocturnal heartburn
and breakthrough)
• Can be taken with or without food
• Better safety profile
Summary Features

49. Disease Dose Duration
Reflux esophagitis (EE) 20mg Once a day 4 to 8 weeks
Maintenance of Healing
Esophagitis
10mg Once a day
-
Gastric Ulcer 20mg Once a Day 8 weeks
Duodenal Ulcer 20mg Once a Day
6weeks
Prevention of NSAID induce
Ulcer
10mg Once a Day -
H. pylori Eradication
20mg Twice daily with triple
drug regimen
01 week
Dosage

50. THANKS