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