Author: name and affiliation
ACID PEPTIC DISORDERS AND
PROTON PUMP INHIBITORS
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DISCLAIMER
PP-NXM-IND-0237 1st Apr 2019
• Acid Peptic Disorders (APDs) and Gastroesophageal Reflux Disease (GERD)
• Epidemiology and Disease Burden
• Pathophysiology and Clinical Presentation
• Diagnosis and Management of GERD
• Proton Pump Inhibitors (PPIs)
Learning Objectives
Introduction to Acid Peptic Disorder (APD)
1
What are Acid Peptic Disorders?
Acid peptic disorder (APD): is a result of acid acting on diminished gastric mucosa
Commonly known manifestations of APD are
Gastroesophageal Reflux Disease (GERD)
Gastritis
Peptic Ulcers
A mucosal defect that extends to or beyond the muscularis
mucosa, with mucosal damage due to pepsin and gastric acid
secretion
Inflammation of gastric mucosal lining due to the action of acid
or H. pylori infection
Egress of gastric contents into the esophagus
H+
H+
H+
H+H+
H+
Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol. 2009;2(3):295-314.
GERD. National Institute of Diabetes and Digestive and Kidney Diseases [Internet]. 2018 [Cited 31 March 2019]. Available from: https://www.niddk.nih.gov/health-information/digestive-diseases/acid-reflux-ger-gerd-adults
Gastritis. National Institute of Diabetes and Digestive and Kidney Diseases [Internet]. 2018 [Cited 31 March 2019]. Available from: https://www.niddk.nih.gov/health-information/digestive-diseases/gastritis
Peptic ulcers. National Institute of Diabetes and Digestive and Kidney Diseases [Internet]. 2018 [Cited 31 March 2019]. Available from: https://www.niddk.nih.gov/health-information/digestive-diseases/peptic-ulcers-stomach-ulcers
GERD: A Chronic APD
Impaired anti-reflux mechanism
Gastric content into esophagus and beyond
Mucosal damage
Heartburn
Other symptoms
Lower
esophageal
sphincter
Diamant NE. Pathophysiology of gastroesophageal reflux disease. GI Motility online. 2006
Asanuma K, et al. Gender difference in gastro-esophageal reflux diseases. World J Gastroenterol. 2016;22(5):1800-10.
Prevalence of GERD
8.8–25.9 %
in Europe
2.5–7.8 % in
East Asia
Significant prevalence across population groups
18.1–27.8 % in
North America
Prevalence is increasing over time
7.6- 19.0% in
India
Did you know?
As most epidemiological estimates of GERD
are symptom-based, the prevalence of
GERD is probably underestimated
El-Serag HB, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871-80.
Bhatia SJ, et al. Epidemiology and symptom profile of gastroesophageal reflux in the Indian population: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol. 2001;30(3):118-27.
World Gastroenterology Organization [Internet]. 2015 [Cited 31 March 2019]. Available from: http://www.worldgastroenterology.org/UserFiles/file/guidelines/gastroesophagel-reflux-disease-english-2015.pdf
Adverse Outcomes
•30.8% patients
experience severe chest
pain in China
•1 in 4 patients may have
anxiety and depression
in China
•$9944 mean total cost
per patient per year, in
USA
•29.4% mean productivity
loss while at work, in USA
Did you know?
In USA, reflux medication use increased 233%
in 10 years- high burden needs awareness now!
Akst LM, et al. The Changing Impact of Gastroesophageal Reflux Disease in Clinical Practice. Ann Otol Rhinol Laryngol. 2017;126(3):229-35.
Stålhammar NO, et al. Partial response to proton pump inhibitor therapy for GERD: observational study of patient characteristics, burden of disease, and costs in the USA. Pragmat Obs Res. 2012;3:57-67.
Zhang L, et al. Health-related quality of life in gastroesophageal reflux patients with noncardiac chest pain: Emphasis on the role of psychological distress. World J Gastroenterol. 2017;23(1):127-34.
Introduction to GERD
2
Pathophysiology
Impaired anti-reflux mechanism
+ Acid hypersecretion
GERD
Histamine receptors
H1 receptors in smooth muscle tissue
H2 receptors in peptic acid secretion
H4 receptors in immune cells
H3 receptors in presynaptic autoregulation
Dysregulation
Did you know?
GERD is not just a peptic disorder, but part of an
impairment of complex web of physiological processes!
Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol. 2006;147(1):S127-35.
Diamant NE. Pathophysiology of gastroesophageal reflux disease. GI Motility online. 2006
Clinical Presentation
•Burning sensation in your chest (heartburn), sometimes spreading to your throat, along with a sour taste in your mouth
•Chest pain
•Difficulty swallowing (dysphagia)
•Dry cough
•Hoarseness or sore throat
•Regurgitation of food or sour liquid (acid reflux)
•Sensation of a lump in your throat
GERD Disease Reference Guide - Drugs.com [Internet]. Drugs.com. 2017 [cited 31 March 2019]. Available from: https://www.drugs.com/mcd/gerd
World Gastroenterology Organization [Internet]. 2015 [Cited 31 March 2019]. Available from: http://www.worldgastroenterology.org/UserFiles/file/guidelines/gastroesophagel-reflux-disease-english-2015.pdf
The Association of Nutrition & Foodservice Professionals [Internet]. 2017 [Cited 31 March 2019]. Available from: https://www.anfponline.org/docs/default-source/legacy-docs/docs/ce-articles/nc072017.pdf
Risk Factors
Dietary and lifestyle
• Obesity, high BMI
• Smoking
• Caffeine, soft drink and alcohol
consumption
• High dietary fat intake
Medications
• Calcium channel blockers
• Anticholinergics
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Bisphosphonates
• Antibiotics
• Potassium supplements
Biological
• Increased secretion of gastrin,
estrogen, progesterone
• Hiatal hernia or scleroderma
• Delayed gastric emptying
Did you know?
GERD is a multifactorial disease, but this also
means that the risk can be managed by
managing risk factors!
Alarm Symptoms
•Dysphagia
•Odynophagia
•Gastric bleeding
•Weight loss
•Anemia
Badillo R, Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther. 2014;5(3):105-12
Katz PO, et al. Corrigendum: guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308-28
Complications
•Esophageal stricture: Formation of scar tissue which narrows the esophagus, causing difficulty swallowing
•Esophageal ulcer: Severely eroded esophageal lining causing an ulcer which may bleed, cause pain and make swallowing difficult
•Precancerous changes (Barrett's esophagus)
GERD Disease Reference Guide - Drugs.com [Internet]. 2018 [Cited 31 March 2019]. Available from: https://www.drugs.com/mcd/gerd
Diagnosis and Management
3
Diagnosis
Classic clinical presentation of GERD
Offer PPIs: Relief indicates GERD
Alarm symptoms
Endoscopy
Suspected GERD
Suspected Barrett’s esophagus
BiopsySymptoms persistent
Ambulatory reflux monitoring
Did you know?
Barium radiographs should not be performed to
diagnose GERD
Katz PO, et al. Corrigendum: guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308-28.
Treatment Options for GERD
Antacids - Offer relief by partial neutralization of gastric hydrochloric acid and
inhibition of the proteolytic enzyme pepsin; Still useful as they are inexpensive, readily available, and safe
H2 Receptor Agonists - Reversible structural analogs of histamine that
cause a decrease in the tonic activation rate of the receptor
Proton Pump Inhibitors (PPIs) - Most potent inhibitors of gastric acid
secretion. They act by inhibiting the gastric H+ K + - ATPase which was identified as the common pathway for acid production
Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol. 2009;2(3):295-314.
American College of Gastroenterology (ACG) 2013 Guidelines for GERD Management
Katz PO, et al. Corrigendum: guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(3):308-28
Lifestyle interventions: weight
loss, changes to sleeping posture,
and dietary elimination foods that trigger reflux
8-week course of PPIs once daily before the first meal of the day
Increase PPI dose to twice daily/ switch
in partial responders
Long-term PPI therapy:
administered in the lowest effective
dose
H2-receptor antagonist as a
maintenance option in patients without erosive disease
Surgical therapy option for long-term
relief in GERD
patients, not recommended
in PPI non-responders
Click here to read the ACG 2013
guidelines
Did you know?
PPIs are the current mainstay of pharmacological
GERD management
Best Practice Recommendations
Best Practice Advice 1: Patients with GERD and acid-related complications (i.e., erosive esophagitis or peptic stricture) should take a PPI for short-term healing and for long-term symptom control
Best Practice Advice 2: Patients with uncomplicated GERD who respond to short-term PPIs should subsequently attempt to stop or reduce them or consider ambulatory esophageal pH/impedance monitoring before committing to lifelong PPIs to help distinguish GERD from a functional syndrome.
Best Practice Advice 3: Patients with Barrett’s esophagus and symptomatic GERD should take a long-term PPI
Best Practice Advice 4: Asymptomatic patients with Barrett’s esophagus should consider a long-term PPI
Best Practice Advice 5: Patients at high risk for ulcer-related bleeding from NSAIDs should take a PPI if they continue to take NSAIDs
Freedberg DE, et al. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-15.
Best Practice Recommendations
Freedberg DE, Kim LS, Yang YX. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-15.
Best Practice Advice 6: The dose of long-term PPIs should be periodically reevaluated so that the lowest effective PPI dose can be prescribed to manage the condition
Best Practice Advice 7: Long-term PPI users should not routinely use probiotics to prevent infection
Best Practice Advice 8: Long-term PPI users should not routinely raise their intake of calcium, vitamin B12 or magnesium beyond the Recommended Dietary Allowance (RDA)
Best Practice Advice 9: Long-term PPI users should not routinely screen or monitor bone mineral density, serum creatinine, magnesium, or vitamin B12
Best Practice Advice 10: Specific PPI formulations should not be selected based on potential risks
Click here to read the AGA 2017
guidelines
Proton Pump Inhibitors (PPIs)
5
What are PPIs?
• PPIs:
•Substituted benzimidazole derivatives that inhibit proton pump (H+/K+ ATPase) in parietal cells of stomach are the primary therapy used to control gastric acid secretions and the widely used PPIs are:
•Commonly used PPIs are;
1989 – FDA approved 1st
PPI, Omeprazole
1995 – FDA approves
Lansoprazole
1999 – FDA approves
Rabeprazole
2000 – FDA approves
Pantoprazole
2001 -Esomeprazole
2001 -Esomeprazole
Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert review of clinical pharmacology. 2009 May 1;2(3):295-314.
Leonard M. Esomeprazole (Nexium™): A New Proton Pump Inhibitor. Pharmacotherapy Update .2001;4(4):1-4.
Mössner J. The indications, applications, and risks of proton pump inhibitors- a review after 25 years. Dtsch Arztebl Int 2016;113: 477–83.
Mechanism of Action
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil. 2013;19(1):25–35.
23
PPIs are prodrug activated by acid and are effective only after
protonation
Protonation activates to form thiophilic drug that reacts with
luminally accessed cysteines on acid pump enzyme
Accumulation in stimulated secretory canaliculus of parietal cell, PPIs bind
to gastric H+, K+-ATPase.
Cys 813 is primary site responsible for inhibition of acid pump enzyme.
Pharmacokinetics and Administration
Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil. 2013;19(1):25–35.
Given ∼30 minutes before meal to ensure that pumps are active when peak concentrations are present in blood
Necessary to protect PPI from gastric acid prior to absorption
PPIs have a relatively short half-life; takes about 3 days to reach steady state inhibition of acid secretion
Pharmacological Properties
Jain KS, et al. Recent advances in proton pump inhibitors and management of acid-peptic disorders. Bioorg Med Chem. 2007;15(3):1181-205.
Generic nameHalf-
life (h)Peak effect (h)
Duration of effect (h)
pKa
Bioavailability (%)
MetabolismExcretion
(%)
Omeprazole 0.7 2 24–72 ∼4 30–40 Extensively U = 77
Hepatic F = 23
Pantoprazole 1 2.5 24–72 ∼4 77 Extensively U = 71
Hepatic F = 18
Lansoprazole 2 1.7 >24 ∼4 80 Extensively U = 35
Hepatic F = 65
Rabeprazole 1 2–5 24 ∼5 52 Extensively U = 90
Hepatic F = 10
Esomeprazole 1.3 1.5 24-27 ∼4 64 Extensively U = 80
Hepatic F = 20
Did you know?
Newer PPIs have higher
bioavailability and longer half-life
Use of PPIs
53.8%-67.7% patients have a medication possession ratio (MPR) of >0.80
70%-84% use PPIs daily
11%-22.2% twice daily PPI use
11.0%-44.8% take GERD medication + PPI
Did you know?
PPIs are one the widest used drugs for the
management of GERD
Hungin AP, et al. Systematic review: Patterns of proton pump inhibitor use and adherence in gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10(2):109-16.
Clinical Outcomes with PPIs
6
Efficacy of PPIs in Randomized Controlled Trials (RCTs)
•Risk of heartburn with PPIs:
•63% less than placebo
•34% less than H2RA
•RR of overall symptom control with PPIs:
•38% less than placebo
•71% less than H2RA
0.37
0.77
0.660.62
0.72
0.29
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
PPIs vs placebo H2RA vs placebo PPIs vs H2RA
Ris
k e
ffe
ct e
xp
resse
d a
s r
ela
tive
ris
k
(RR
)
Heartburn remission Overall symptom control
Did you know?
Relative Risk (RR) measures the risk/incidence
of a particular event e.g. heartburn or of no
symptom relief
Sigterman KE, et al. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev. 2013;(5):CD002095.
Efficacy of PPIs in RCTs
Maintenance dose:
•PPIs perform better than H2RA (p=0.003) and prokinetic (p=0.02) either alone or in combination with other drugs
49
80
66
89
0
10
20
30
40
50
60
70
80
90
100
H2RA PPIs Prokinetic +H2RA
PPI+Prokinetic
Pe
rce
nta
ge
of p
atie
nts
Maintenance of remission N=175 (35 patients in each treatment group)
Did you know?
Based on available evidence, empiric
therapy with PPIs in the short-term and as
maintenance therapy are both “Strong
recommendations” from ACG
Vigneri S, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995;333(17):1106-10.
Safety of PPIs
•Increased risk of fractures (Modest increase in risk with long-term use)
•QT prolongation with hypokalemia (Rarely occurs with prolonged use risk)
•Vitamin B12 and iron deficiency (Risk with chronic use)
•Community acquired pneumonia (Small increase in risk)
Did you know?
PPIs are generally well tolerated
Safety of Long-Term PPI Use. JAMA. 2017;318(12):1177-8.
Improvement in QoL
Improvement in all Quality of Life (QoL) Reflux and Dyspepsia Questionnaire Subscales
• Sleep disturbance (Mean increase : 0.65 in 8 weeks)
• Food/drink problems (Mean increase : 1.07 in 8 weeks)
• Vitality (Mean increase : 0.79 in 8 weeks)
• Physical/social functioning (Mean increase : 0.50 in 8 weeks)
• Total score (Mean increase: 0.77 in 8 weeks)
Did you know?
QoLRAD questionnaire is a QoL
questionnaire specific to reflux and
dyspepsia.
Gunasekaran T, et al. Effects of esomeprazole treatment for gastroesophageal reflux disease on quality of life in 12- to 17-year-old adolescents: an international health outcomes study. BMC Gastroenterol. 2009;9:84.
• Emotional distress (Mean increase: 0.83 in 8 weeks)
PPI Failure
•Although PPIs are very effective in treating APDs- clinical failure is still seen in GERD patients -PPI failure
•Overall prevalence of failure-30%
•40-50% on NERD
•6-15% from ERD
•20% from Barretts esophagus
•Could be due to
•Poor compliance
•Delayed gastric emptying
•Visceral hypersensitivity
Did you know?
PPI non-responders experience the
burden of GERD despite being on PPI
Fass R, et al. Systematic review: proton‐pump inhibitor failure in gastro‐oesophageal reflux disease–where next?. Aliment Pharmacol Ther. 2005;22(2):79-94.
A Look Back
•GERD is caused by the egress of gastric contents into the esophagus
•GERD has a growing prevalence and is rapidly becoming an important health burden
•GERD is diagnosed and managed by starting patients on PPI trial
•PPIs are the mainstay of GERD management
•Long-term administration of GERD should be done at the lowest possible dose
•PPIs are efficacious, are well tolerated and improve QoL in patients with GERD
Before We Thank You…
•Thanks for your journey with us. Before you go, Walter, your colleague needs your help to resolve the mess of papers on his table. Could you help him by labelling the papers with the right keywords, so that he can sort them?
…..it was the first
PPI to have been
approved by FDA, in
1989.
Omeprazole
This amino acid
binds with PPIs and
allows for the anti
secretory functions of
PPIs .
Cys183
There is a 63% less
risk of this GERD-
related clinical
outcome with the use
of PPIs vs placebo
Heartburn
Weight loss, changes
to sleeping posture,
and dietary
elimination of triggers
etc are these type of
changes
Lifestyle
That is right!
Omeprazole was the
That is right! Cys 183
provides the Sulfur
That is right! PPIs
significantly reduce
That is right! With the
right therapy, and
right approach to
Thank You