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Presented by: Drena Chua Hui Yi
Gan T.Y
Lam Hoi Sun
Pea H. L
Wong K. Y
Gastrointestinal Diseases
Contents
 Describe heartburn
 Describe GERD (Gastroesophageal Reflux
Disease) – pathophysiology and sign& symptoms
 Describe PPI (proton pump inhibitors) – MOA,
pharmacokinetics, adverse effects
 Non- pharmacological and pharmacological
treatments
 Research Findings
 Current research
 Q & A
Research Finding
Heartburn
Heartburn
 a painful burning sensation in the chest and throat
 along with a sour or bitter taste in the throat and
mouth
 Symptoms are often worsened after heavy meals,
leaning forward, or lying flat
 The feeling can last for a few minutes or a few hours.
Heartburn
What if this symptom is worsen ?
Hint:Morethan3timesaweek
Gastroesophageal
Reflux Disease (GERD)
WHAT IS GERD ???
A chronic condition in which the stomach
contents leak backwards from the stomach
into the esophagus.
This can irritate the esophagus and cause
heartburn and other symptoms.
This can leads to many chronic and acute
symptoms.
Symptoms of GERD
 Heartburn,
 Nausea.
 Regurgitation - dyspepsia
 Difficulty swallowing - dysphagia
 Frequent sore throat.
 Coughing, wheezing
Let’s Refresh!
How does acid reflux occur?
 When eating, food passes from the throat through
the esophagus and into the stomach.
 A fibrous muscular ring in the lower esophagus
called lower esophageal sphincter (LES) prevents
the food from returning back to the esophagus.
 LES become weak/ loosen in GERD patients
 This allows digestive juices to leak back into the
esophagus which irritates the esophageal lining.
Prolonged Exposure May
Cause Esophagus to:
 Become inflamed, with risk of having
esophagitis.
 Become narrow
 Develop an open sore (ulceration).
Research Finding
“Wdhd-2008-Map-of-Digestive-Disorders.pdf.” Accessed May 29, 2016.
http://www.worldgastroenterology.org/UserFiles/file/wdhd-2008-map-of-digestive-disorders.pdf.
Factors that Weaken or Loosen
Esophageal Sphincter:
 Smoking
 Alcohol
 Increased abdominal pressure caused by obesity or
pregnancy
 A bulge in the stomach (hiatal hernia) that
protrudes above the diaphragm
 Certain food (spicy, chocolate, peppermint,
caffeine).
 Drug- drug interactions
Common Medication For
Treatment
1. Proton pump inhibitor (PPI)
2. Histamine H2 antagonist
3. Antacid
Mechanism of action
Proton Pump Inhibitors
 They are prodrug (inactive form) which is
neutrally charged (lipophilic) with pKa 4-5
 They readily across stomach cell membranes
with acidic environments
 It is protonated and rearranges into its active
form in acid
 It covalently and irreversibly bind to the gastric
proton pump, deactivating the acid production
Example of PPIs
 Omeprazole
 Lansoprazole
 Pantoprazole
 Rabeprazole
 Esomeprazole
 Dexlansoprazole
Extended Release
Immediate Release
Chemical Structures of PPI
Related Video
• Prodrug PPI is taken orally
and enters in stomach.
• Inactivated PPI is
protonated with presence
of H+ into activated form.
• Sulphenamide
intermediate (SN) is
formed which is very
reactive and readily to
bind covalently with
sulfhydryl groups (SH) in
proton pumps
• This binding inhibits acid
secretion by proton pump
– no exchange of H+ and
K+
Pharmacokinetics of PPI - Omeprazole
 Peak plasma levels: 0.5 – 3.0 hrs
 Bioavailability: decreased by 50% with meal
taken.
 Recommend take it 30 minutes before having
meal
 Distribution: Protein binding Is 95%
 Undergo rapid first pass metabolism
 Elimination half life : 0.5 – 2.0 hrs
 Duration of action : 24 hrs
Drug-drug Interactions
 Hepatic CYP-mediated oxidative metabolism. Alter drug
metabolism by induction or inhibition of the cytochrome
P450 enzymes.
 Gastric acid secretion decreased by PPIs can influence the
absorption of other.
 Greater potential: Omeprazole, esomeprazole and
lansoprazole.
 Lower potential: Pantoprazole.
Research Finding
http://archinte.jamanetwork.com/article.aspx?articl
eid=2481157
http://well.blogs.nytimes.com/2016/02/17/heartburn-drugs-tied-to-dementia-risk/
http://archneur.jamanetwork.com/article.aspx?articleid=2487379#tab3
What it is about ?
Common Effects of PPs
1. Headache
2. Stomach Pain
3. Nausea
4. Diarrhea
5. Vomiting
6. Constipation
Long Term Effects of PPIs
 Deficiency of Vitamin B12
 Deficiency of iron
 Decreased calcium absorption
 Osteoporosis
 Pneumonia
 Clostridium difficile colitis
 Hypomagnesemia
 Acute Interstitial nephritis
Deficiency of Vitamin B12
 VB12 is found in wide variety of animal foods
 Keep body nerve & body cell healthy, aid in the
production of DNA, formation of RBC
 Gastric acid secretion required for the body to
absorb VB12.
 PPI reduce secretion of gastric acid, reduce
absorption of VB12.
 Lack of VB12 causes weakness in body , anaemia
and loss of balance
Deficiency of Iron
Iron present in the food is in either heme-iron or non
heme-iron
Heme-iron directly absorb via heme transporter to
the duodenum
Non heme-iron convert from (Fe3+) to (Fe2+) for
absorption into duodenum
Conversion happen in acidic environment
Gastric acid enhance the solubility and prevent
precipitation of insoluble Fe3+
PPI drug increase the pH of stomach
Resulting gastric environment to be more alkaline
In alkaline environment, promotes the oxidation of
(Fe2+) to (Fe3+)
When pass through the duodenum, iron will not be
absorb
Precipitation of ferric iron happens
Lack of iron causes fatigue, dizziness, lowered
immunity and anaemia
Associated with hypomagnesaemia
 Abnormally low level of magnesium in blood
 Due to PPI affects the gastrointestinal
absorption of magnesium
 Increased Ach release (PNS)
 May cause cardiac complications,
arrhythmias
 Associated with hypocalcaemia
Increased the risk of C. difficile
 A type of infection in the colon
caused by Clostridium difficile
bacteria
 Produce toxins that damage the
lining of colon
Increased risk of having AIN
 Acute Interstitial Nephritis
 Kidney tubules become swollen (inflamed) that occur
suddenly for a temporary period.
 Mostly occurred during drug-drug interaction, i.e. with
antibiotics (penicillin) that leads to AIN or long term
used PPI
Current Research
“Common Heartburn Drugs Linked to Kidney Disease in Study: MedlinePlus.” Accessed May 29, 2016.
https://www.nlm.nih.gov/medlineplus/news/fullstory_158313.html.
Other Treatment
Others Medications
1. Mucosal Protectants (Sucralfate)
2. Prokinetic agents
3. Potassium-competitive Acid Blockers (misoprostol)
4. Gastrin Receptors antagonist (Metoclopramide)
Antireflux Surgery
 Hiatal Hernia problem
 Tightening the opening
in diaphragm to keep
stomach
 Wrap the upper part of
stomach with stitches.
 The stitches helps prevent
stomach acid and food from
flowing back into the esophagus.
Is the PPIs the best treatment?
 PPIs really worked in treatment of GERD, but many
people have trouble discontinuing because the amount
of acid in their digestive system surges when they stop
taking the drug.
 Clinicians, pharmacists and patients have to weight
the benefits against the potential side effects.
 Future studies will help to better inform these
decisions.
Q & A session
1. What is the real causes of gastroesophageal reflux disease (GERD) ?
(i) Heartburn
(ii) Histal Hernia
(iii) Weak Lower Esophageal Sphincter (LES)
(iv) Too less acid
A. I , ii, iii
B. I . Iii .iv
C. Ii , iii , iv
D. All of above
2. What is the correct sequences of mechanism action of PPIs ?
P – Sulfoxide group in PPI is converted into activated form
of sulfonamide intermediate
Q –PPI which is prodrug are activated by acid in stomach
R –Enzyme-inhibitor complex is formed by binding to sulfhydryl
residue in proton pump
S – Their inhibition effect on acid secretion is exerted
A. P,Q,R,S
B. Q,P,R,S
C. S,P,R,Q
D. Q,R,S,P
3. Which one of the following are the latest
medication on treating GERD ?
(i) GABAB receptor agonists
(ii) Cannabinoid receptor agonists
(iii) Potassium-competitive acid blockers
(iv) CCK (cholecytokinin) antagonists
A. I, ii, iii
B. ii, iii, iv
C. I, iii, iv
D. All of above
4. Which one of the following is the common side effect of
having PPIs for long term use?
(I) hypomagnesaemia
(II) Acute Interstitial Nepritis
(III) Deficiency of Vitamin B12
(IV) Dementia
A. I, II, III
B. I,III,IV
C. II, III, IV
D. All of above
Is Proton pump inhibitors (PPIs) the best treatment for Gastroesophageal Reflux Disease (GERD) ?

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Is Proton pump inhibitors (PPIs) the best treatment for Gastroesophageal Reflux Disease (GERD) ?

  • 1. Presented by: Drena Chua Hui Yi Gan T.Y Lam Hoi Sun Pea H. L Wong K. Y
  • 3. Contents  Describe heartburn  Describe GERD (Gastroesophageal Reflux Disease) – pathophysiology and sign& symptoms  Describe PPI (proton pump inhibitors) – MOA, pharmacokinetics, adverse effects  Non- pharmacological and pharmacological treatments  Research Findings  Current research  Q & A
  • 6. Heartburn  a painful burning sensation in the chest and throat  along with a sour or bitter taste in the throat and mouth  Symptoms are often worsened after heavy meals, leaning forward, or lying flat  The feeling can last for a few minutes or a few hours.
  • 8. What if this symptom is worsen ? Hint:Morethan3timesaweek
  • 10. WHAT IS GERD ??? A chronic condition in which the stomach contents leak backwards from the stomach into the esophagus. This can irritate the esophagus and cause heartburn and other symptoms. This can leads to many chronic and acute symptoms.
  • 11. Symptoms of GERD  Heartburn,  Nausea.  Regurgitation - dyspepsia  Difficulty swallowing - dysphagia  Frequent sore throat.  Coughing, wheezing
  • 13.
  • 14. How does acid reflux occur?  When eating, food passes from the throat through the esophagus and into the stomach.  A fibrous muscular ring in the lower esophagus called lower esophageal sphincter (LES) prevents the food from returning back to the esophagus.  LES become weak/ loosen in GERD patients  This allows digestive juices to leak back into the esophagus which irritates the esophageal lining.
  • 15. Prolonged Exposure May Cause Esophagus to:  Become inflamed, with risk of having esophagitis.  Become narrow  Develop an open sore (ulceration).
  • 16.
  • 17. Research Finding “Wdhd-2008-Map-of-Digestive-Disorders.pdf.” Accessed May 29, 2016. http://www.worldgastroenterology.org/UserFiles/file/wdhd-2008-map-of-digestive-disorders.pdf.
  • 18. Factors that Weaken or Loosen Esophageal Sphincter:  Smoking  Alcohol  Increased abdominal pressure caused by obesity or pregnancy  A bulge in the stomach (hiatal hernia) that protrudes above the diaphragm  Certain food (spicy, chocolate, peppermint, caffeine).  Drug- drug interactions
  • 19. Common Medication For Treatment 1. Proton pump inhibitor (PPI) 2. Histamine H2 antagonist 3. Antacid
  • 21. Proton Pump Inhibitors  They are prodrug (inactive form) which is neutrally charged (lipophilic) with pKa 4-5  They readily across stomach cell membranes with acidic environments  It is protonated and rearranges into its active form in acid  It covalently and irreversibly bind to the gastric proton pump, deactivating the acid production
  • 22. Example of PPIs  Omeprazole  Lansoprazole  Pantoprazole  Rabeprazole  Esomeprazole  Dexlansoprazole Extended Release Immediate Release
  • 25. • Prodrug PPI is taken orally and enters in stomach. • Inactivated PPI is protonated with presence of H+ into activated form. • Sulphenamide intermediate (SN) is formed which is very reactive and readily to bind covalently with sulfhydryl groups (SH) in proton pumps • This binding inhibits acid secretion by proton pump – no exchange of H+ and K+
  • 26.
  • 27. Pharmacokinetics of PPI - Omeprazole  Peak plasma levels: 0.5 – 3.0 hrs  Bioavailability: decreased by 50% with meal taken.  Recommend take it 30 minutes before having meal  Distribution: Protein binding Is 95%  Undergo rapid first pass metabolism  Elimination half life : 0.5 – 2.0 hrs  Duration of action : 24 hrs
  • 28. Drug-drug Interactions  Hepatic CYP-mediated oxidative metabolism. Alter drug metabolism by induction or inhibition of the cytochrome P450 enzymes.  Gastric acid secretion decreased by PPIs can influence the absorption of other.  Greater potential: Omeprazole, esomeprazole and lansoprazole.  Lower potential: Pantoprazole.
  • 29.
  • 33. What it is about ?
  • 34. Common Effects of PPs 1. Headache 2. Stomach Pain 3. Nausea 4. Diarrhea 5. Vomiting 6. Constipation
  • 35. Long Term Effects of PPIs  Deficiency of Vitamin B12  Deficiency of iron  Decreased calcium absorption  Osteoporosis  Pneumonia  Clostridium difficile colitis  Hypomagnesemia  Acute Interstitial nephritis
  • 36. Deficiency of Vitamin B12  VB12 is found in wide variety of animal foods  Keep body nerve & body cell healthy, aid in the production of DNA, formation of RBC  Gastric acid secretion required for the body to absorb VB12.  PPI reduce secretion of gastric acid, reduce absorption of VB12.  Lack of VB12 causes weakness in body , anaemia and loss of balance
  • 37. Deficiency of Iron Iron present in the food is in either heme-iron or non heme-iron
  • 38. Heme-iron directly absorb via heme transporter to the duodenum Non heme-iron convert from (Fe3+) to (Fe2+) for absorption into duodenum Conversion happen in acidic environment Gastric acid enhance the solubility and prevent precipitation of insoluble Fe3+ PPI drug increase the pH of stomach Resulting gastric environment to be more alkaline
  • 39. In alkaline environment, promotes the oxidation of (Fe2+) to (Fe3+) When pass through the duodenum, iron will not be absorb Precipitation of ferric iron happens Lack of iron causes fatigue, dizziness, lowered immunity and anaemia
  • 40. Associated with hypomagnesaemia  Abnormally low level of magnesium in blood  Due to PPI affects the gastrointestinal absorption of magnesium  Increased Ach release (PNS)  May cause cardiac complications, arrhythmias  Associated with hypocalcaemia
  • 41. Increased the risk of C. difficile  A type of infection in the colon caused by Clostridium difficile bacteria  Produce toxins that damage the lining of colon
  • 42. Increased risk of having AIN  Acute Interstitial Nephritis  Kidney tubules become swollen (inflamed) that occur suddenly for a temporary period.  Mostly occurred during drug-drug interaction, i.e. with antibiotics (penicillin) that leads to AIN or long term used PPI
  • 43. Current Research “Common Heartburn Drugs Linked to Kidney Disease in Study: MedlinePlus.” Accessed May 29, 2016. https://www.nlm.nih.gov/medlineplus/news/fullstory_158313.html.
  • 44.
  • 46. Others Medications 1. Mucosal Protectants (Sucralfate) 2. Prokinetic agents 3. Potassium-competitive Acid Blockers (misoprostol) 4. Gastrin Receptors antagonist (Metoclopramide)
  • 47. Antireflux Surgery  Hiatal Hernia problem  Tightening the opening in diaphragm to keep stomach  Wrap the upper part of stomach with stitches.  The stitches helps prevent stomach acid and food from flowing back into the esophagus.
  • 48.
  • 49. Is the PPIs the best treatment?  PPIs really worked in treatment of GERD, but many people have trouble discontinuing because the amount of acid in their digestive system surges when they stop taking the drug.  Clinicians, pharmacists and patients have to weight the benefits against the potential side effects.  Future studies will help to better inform these decisions.
  • 50. Q & A session
  • 51. 1. What is the real causes of gastroesophageal reflux disease (GERD) ? (i) Heartburn (ii) Histal Hernia (iii) Weak Lower Esophageal Sphincter (LES) (iv) Too less acid A. I , ii, iii B. I . Iii .iv C. Ii , iii , iv D. All of above
  • 52. 2. What is the correct sequences of mechanism action of PPIs ? P – Sulfoxide group in PPI is converted into activated form of sulfonamide intermediate Q –PPI which is prodrug are activated by acid in stomach R –Enzyme-inhibitor complex is formed by binding to sulfhydryl residue in proton pump S – Their inhibition effect on acid secretion is exerted A. P,Q,R,S B. Q,P,R,S C. S,P,R,Q D. Q,R,S,P
  • 53. 3. Which one of the following are the latest medication on treating GERD ? (i) GABAB receptor agonists (ii) Cannabinoid receptor agonists (iii) Potassium-competitive acid blockers (iv) CCK (cholecytokinin) antagonists A. I, ii, iii B. ii, iii, iv C. I, iii, iv D. All of above
  • 54. 4. Which one of the following is the common side effect of having PPIs for long term use? (I) hypomagnesaemia (II) Acute Interstitial Nepritis (III) Deficiency of Vitamin B12 (IV) Dementia A. I, II, III B. I,III,IV C. II, III, IV D. All of above

Editor's Notes

  1. When you eat, food passes from the throat to the stomach through the esophagus. A ring of muscle fibers in the lower esophagus prevents swallowed food from moving back up. These muscle fibers are called the lower esophageal sphincter (LES). When this ring of muscle does not close all the way, stomach contents can leak back into the esophagus. This is called reflux or gastroesophageal reflux. Reflux may cause symptoms. Harsh stomach acids can also damage the lining of the esophagus.
  2. SH group also knowns as cysteine residue
  3. S=O sulfoxide group
  4. The study is in JAMA Neurology
  5. Chronic or acute condition, specific and monitoring in drug usage is recommending. patients who require a PPI for appropriate indications, at the lowest dose, and for the shortest time possible care 1-For complicated acid-peptic disease, dose reduction or cessation of PPI therapy may not be possible. 2-If the PPI was prescribed only for symptom relief, as in cases of dyspepsia or no erosive gastroesophageal reflux disease, reduce the dose of PPI to as low as possible to maintain symptom control.
  6. Several directions in drug development have been pursued in patients who failed PPI treatment. These include more early and profound acid suppression, reduction in the rate of TLESRs, improving esophageal and/or gastric motility, attenuation of esophageal pain and mucosal coating of the esophagus.