1. Indications of Proton Pump Inhibitors
Samir Haffar M.D.
Assistant Professor of Gastroenterology
Al-Mouassat University Hospital – Damascus – Syria

2. Carl Schwartz: 1910

3. Strategies used during the 20th century for
counteracting action of gastric acid
Inflexion occurs during the 1980s
with introduction of drugs inhibiting gastric acid secretion
Dı az-Rubio M. Drugs 2005 ; 65 (Suppl. 1) : 1 – 6.

4. “Potent acid inhibition”
• pH > 4 1000-fold ↓ H concentration in stomach
Reduced the pepsin activity
• At least 16 h No clear evidence to 16 h as cut-off
Used in many studies
Described arbitrarily as maintaining an intragastric
pH > 4 for at least 16 h out of every 24 h

5. 0
20
40
60
80
100
Maximum pepsin activity
(%)
1 2 3 4
Gastric juice pH
pH 4 is a critical threshold for
gastric pepsin activity
Adapted from Berstad 1970

6. H2RA or PPIs?
No indications for H2RA in present day
digestive diseases, perhaps with the exception of
Gomollón1 F & Calvet X . Drugs 2005; 65 Suppl. 1: 25 – 33.
• Management of occasional heartburn
Possibly in association with an antacid
• Exceptional patient who is allergic to all PPIs

7. PPIs are one of the most frequently prescribed
classes of drug in the world because of:
 High level of efficacy
 Low toxicity
 Reduced cost
 Lack of alternative therapies

8. Sales of PPI & H2RA in USA & Italy
United States Italy
Corleto VD. Aliment Pharmacol Ther 2001 ; 15 : 1555 – 1561.
Sales of PPI reach > 50% of entire market of
gastric antisecretory drugs in both countries by 1998

9. Six available PPIs
Generic name Trade name Daily dose Route
Delayed release PPIs
Omeprazole Losec® – Prilosec® 20 mg Oral
Lanzoprazole Lanzor – Prevacid® 30 mg Oral – IV
Pantoprazole Protonix® 40 mg Oral – IV
Rabeprazole Aciphex® – Pariet® 20 mg Oral
Esomeprazole Nexium® 40 mg Oral – IV
Are all PPIs the same?
Immediate release PPIs
OMP Na bicarbonate Zegerid Oral

10. Intragastric pH control in patients with GERD
Katz PO. Rev Gastroenterol Disord. 2003; 3(2): 59 - 69.
Gain from 20% to 40% is achieved when comparing
esomeprazole with other PPIs

11. Helpful facts on the use of PPIs
• Take twice daily for first 2 – 3 days of therapy
Steady state is not reached for a couple of days
• First dose should be before breakfast
• Second dose, if used, should be before dinner
• Not likely to be effective when used as required
Wolfe MM, Sachs G. Gastroenterology 2000; 118: S9 -S31.

12. Hierarchy of intragastric pH control
• PPI once a day
• PPI once a day plus H2RA
• PPI bid
• PPI bid + H2RA

13. Indications of potent acid inhibition
 GERD: need more acid inhibition than PU
 Helicobacter Pylori eradication
 Peptic ulcer: gastric – duodenal – bleeding PU
 Prevention & treatment of NSAID-induced lesions
 Functional Dyspepsia
 ↑Gastric acid : ZES - mastocytosis - retained antrum

14.  PPIs & GERD

15. Healing rates in erosive esophagitis
4 –12week of treatment
Meta-analysis of > 2000 patients assessing 4 - 12week
healing rates in patients with erosive esophagitis
Chiba N et al. Gastroenterology. 1997; 112: 1798 - 1810.

16. Healing rates of erosive esophagitis
according to LA Grade
Richter et al. Am J Gastroenterol 2001; 96 : 656 – 665.
P = 0.001

17. Maintenance of healing of erosive esophagitis
Lauritsen K et al. Aliment Pharmacol Ther. 2002;17:333-341.

18. Underlying mechanisms for persistent
heartburn despite treatment with PPIs
Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.
10 – 40 % of patients

19. Combined MII-pH of the esophagus
Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.
Weakly acidic reflux Weakly alkaline reflux

20. Endoscopic images of eosinophilic esophagitis
Linear furrows &
adherent white exudatesConcentric rings
Small calibre esophagus
with stricture
Mucosal laceration from
diagnostic endoscopy

21.  PPIs & HP eradication

22. PPI & HP eradication
• Single dose of PPIs reduces efficacy of HP eradication
PPIs should be used at double the standard doses
Exception of esomeprazole: 20mg bid is effective
• No data available that might suggest one PPI to be
preferable to another in this indication

23.  PPIs & peptic ulcers:
Gastric – duodenal – bleeding

24. Medical therapy for gatric & duodenal ulcer
• Removing injurious agent: NSAIDs or HP
• Standard dose of PPI suffices
• Double dose in some cases particularly in gastric ulcer
• No comparative studies between various PPIs

25. Stage Characteristics Rebleeding
I a Jet arterial bleeding 90 %
Ib Oozing 50 %
IIa Visible Vessel 25 – 30 %
IIb Adherent clot 10 – 20%
IIc Black spot in ulcer crater 7 – 10%
III Clean base ulcer 3 – 5 %
Forrest’s classification for PU bleeding

26. Forrest’s classification for bleeding PU
III (clean base)II-b (adherent clot)
II-a (visible vessel)I-b (oozing)
II-c (black spot)
I-a (arterial jet )

27. MA of PPI in UGI bleeding before endoscopy
4 RCTs – 1 512 patients
• Excluding pts suspected of having variceal bleeding
• Rebleeding OR 0.81; 95% CI (0.61–1.09)
• Endoscopic tt at subsequent index endoscopy
OR 0.93, 95% CI (0.53–1.64)
• Surgery OR 0.96, 95% CI (0.68–1.35)
• Mortality OR 1.12; 95% CI (0.72–1.73)
Dorward S et al. Cochrane Database Syst Rev 2006;(4):CD005415.

28. PPI & bleeding PU
* Barkun A et al. Ann Intern Med 2003 ;139 : 843 – 57.
** Leontiadis GI et al. Gastroenterol Clin N Am 2009 ; 38 : 199 – 213.
*** Kaviani MJ et al. Aliment Pharmacol Ther 2003 ; 17 : 211 – 6.
Controversial issues**
• Dose No uniform consensus
• Route Omeprazole 40 mg bid PO effective***
Consensus recommendations*
• Initially 80 mg bolus
• Followed by Infusion of 8 mg/hr for 72 hrs
• After 72 h Equivalent to omeprazole 40 mg bid
if oral intake is resumed

29. MA of PPIs in peptic ulcer bleeding
24 RCTs – 4373 patients included
Leontiadis GI et al. Cochrane Database Syst Rev 2006;(1):CD002094.
MortalityRebleeding – NNT 13

30.  PPIs & NSAIDs

31. Serious GI Events
Clinical Ulcers
Endoscopic Ulcers
Relative Severity
GI Symptoms
Relative Frequency
NSAID-related GI side effects

32. Choice between various NSAIDs dominated
by uneasy application of
‘least harm principle’
balancing various potential adverse events

34. Risk factors for GI complications in NSAIDs users
Ranked in terms of importance
• Prior history of complicated ulcers
• Concomitant use of anticoagulants
• Multiple NSAID use, including low-dose aspirin
• Prior history of uncomplicated ulcer
• High NSAID dose (or use of piroxicam or ketorolac)
• Age > 60 years
• Severe illness
• Helicobacter pylori infection
• Concomitant use of corticosteroids

35. Prevention strategies of GI risk due to NSAIDs
• Best way: avoid NSAID & substitute with acetaminophen
• Use “safer” NSAID:
C2SI, diclofenac, aceclofenac, ibuprofen
• Avoid of NSAID with highest GI toxicity
Ketorolac, piroxicam, ketoprofen
• Use lowest effective dose for shortest period of time
• Avoid concomitant therapy with
Anticoagulants, corticosteroids, low-dose aspirin, APT
• Eradicate HP infection in patients with prior ulcer history
Sostres C et al Best Pract Res Clin Gastroenterology 2010 ; 24 : 121 – 132.

36. Patients at increased risk for NSAIDs GI toxicity
High risk 1. History of complicated ulcer especially recent
2. Multiple (> 2 risk factors)
HP is independent & additive risk factor & addressed separately
ACG guidelines for prevention of NSAID-related ulcer complications .
Am J Gastroenterol 2009 ; 104: 728 – 738.
Moderate risk
(1 – 2 risk factors)
1. Age > 65 years (OR 2.0 – 3.5)
2. High dose NSAID therapy (OR 8.0)
3. Previous history of uncomplicated ulcer
4. Concurrent use of aspirin
5. Concurrent use of corticosteroids (OR 2.0)
6. Concurrent use of anticoagulants (OR 3.0)
Low risk No risk factors

37. Patients at increased risk for NSAIDs CV toxicity
High risk Patients with risk factors for CV disease often
receive prophylactic aspirin
Arbitrarily defined as requirement for low-dose
aspirin for prevention of serious CV events
Low risk No risk factors

38. Prevention of NSAID-related ulcer complications
Low GI risk Moderate GI risk High GI risk
Low CV risk NSAID alone
(least ulcerogenic
at lowest dose)
NSAID
+
PPI/misoprostol
Alternative therapy
or
C2SI + PPI/misoprostol
Patients with ulcer history: search for HP & if present eradicated
Naproxen may have some cardioprotective properties
ACG guidelines for prevention of NSAID-related ulcer complications.
Am J Gastroenterol 2009 ; 104: 728 – 738.
High CV risk Naproxen
+
PPI/misoprostol
Naproxen
+
PPI/misoprostol
Avoid NSAIDs & C2SI
Use alternative therapy

39. GI safety of non-selective NSAIDs
RR of different NSAIDs could differ 10-fold
* Risk at higher doses (> 1.5 –2.4 g/d) comparable to others NSAIDs
Br Med J 1996 ; 312 : 1563 – 1566.
Lowest risk Ibuprofen *
Diclofenac
Moderate risk Indomethacin
Naproxen
Sulindac
Aspirin
Highest risk Azapropazone
Tolmetin
Ketoprofen
Piroxicam
Longer half-time

40. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• 18 experts from 10 European countries
• Published English-language literature from 1998 to 2008
• Method: Research & Development/UCLA(RAND/UCLA)
• Three panel meeting: January, June, &November 2008
• 144 different patient profiles & 10 treatment options
• Statement: Appropriate – Uncertain – Inappropriate
• Coordinated by Center for Decision Analysis & Support
• Supported by Pfizer Inc
http://www.e-hims.com/Sensar/

41. European expert panel on appropriate use of NSAID
Name Speciality Country
1- Gerd R Burmester Rheumatology Germany
2-Francis Berenbaum Rheumatology France
3- Ferdinand Breedveld Rheumatology The Netherlands
4- Maxime Dougados Rheumatology France
5- Emilio Martín Mola Rheumatology Spain
6- Ignazio Olivieri Rheumatology Italy
7- Josef Smolen Rheumatology Austria
8- Stefan Lohmander Orthopaedics Sweden
9- Luigi M Biasucci Cardiology Italy
10- Matthias Hermann Cardiology Switzerland
11- Tom MacDonald Cardiology and Clinical Pharmacology UK
12- Chris Hawkey Gastroenterology UK
13- Angel Lanas Gastroenterology Spain
14- Carmelo Scarpignato Gastroenterology and Clinical Pharmacology Italy
15- Adam Bajkowski Family Medicine UK
16- Peter Dieleman Family Medicine Belgium
17- Tony Mets Geriatrics Belgium
18- Nele Van Den Noortgate Geriatrics Belgium

42. http://www.e-hims.com/Sensar/

43. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• Given complexity of data & to avoid oversimplification:
Electronic tool may offer best opportunities as quick
reference guide to panel results
• In the complex and dynamic area of NSAID use:
Such approach offer best chances of benefiting from
perspective of both science & practice
http://www.e-hims.com/Sensar/
Burmester G et al. Ann Rheum Dis 2011 ; 70 : 818 – 822.

44. Major GI bleeding in low dose aspirin
14 RCTs – over 57 000 patients
McQuaid KR et all. Am J Med 2006 ; 119 : 624 – 638.
Major GI bleeding: fatal – hospitalization – transfusion
Low dose asipirin: 75 – 325 mg/day
NNH during 1 year period: 833

45.  PPIs & dyspepsia

46. Functional dyspepsia
• Persistent or recurrent pain or discomfort centered in the
upper abdomen for more than 12 weeks in the preceding
12 months with no evidence of an organic disease that is
likely to explain the symptoms
• Divided into 4 symptom groups: Ulcer-like
Reflux-like
Dysmotility-like
Unspecified

47. Alarm features in dyspepsia (red flags)
• Age > 55 years with new-onset dyspepsia
• Family history of UGI cancer
• Unintended weight loss
• Gastrointestinal bleeding
• Progressive dysphagia or odynophagia
• Unexplained iron-deficiency anemia
• Persistent vomiting
• Palpable mass or lymphadenopathy
• Jaundice
AGA technical review on evaluation of dyspepsia.
Gastroenterology 2005 ; 129 : 1756 – 80.


48. PPI versus placebo in uninvestigated dyspepsia
MA of 4 RCTs
AGA technical review on evaluation of dyspepsia.
Gastroenterology 2005 ; 129 : 1756 - 80.

49. PPI versus placebo in nonulcer dyspepsia
MA of 8 RCTs
AGA technical review on evaluation of dyspepsia.
Gastroenterology 2005 ; 129 : 1756 - 80.

50.  PPIs & Zollinger-Ellison syndrome

51. Suspicion of ZES
• Refractory erosive esophagitis
• Multiple peptic ulcers
• Ulcers in distal duodenum or jejunum
• Complicated ulcers
• Recurrent ulcers after acid-reducing surgery
• Ulcers associated with diarrhea
• Family history of MEN-1

52. Diagnosis of ZES

53. Treatment of ZES
• Surgery Gastrinoma enucleation
Parietal cell vagotomy
Total gastrectomy (abandoned)
• PPI Control acid secretion in most patients
Very high doses (eg, omeprazole 120mg/day)
BAO < 10 mEq/h 1 hour before next dose
< 5 mEq/h in prior gastric surgery
Schubert ML & Peura D A. Gastroenterology 2008 ; 134 : 1842 – 1860.

54. Referrals & diagnosis of new cases of ZES
in 2 centers after widespread use of PPIs
Corleto VD. Aliment Pharmacol Ther 2001 ; 15 : 1555 – 1561.

55. Retained antrum syndrome
Hauser SC et al. Mayo clinic gastroenterology & hepatology board review.
Mayo Clinic Scientific Press, Rochester, USA, 3rd edition, 2008.
Retained antral
tissue with gastrin
secreting cells

56. What dose of PPIs?
Generic name Standard dose
(mg/day)
Refractory patient
(mg/day)
Omeprazole 20 mg 80 mg
Lanzoprazole 30 mg 120 mg
Pantoprazole 40mg 160 mg
Rabeprazole 20 mg 80 mg
Esomeprazole* 40 mg 80 mg
* Therapeutic advantage of esomeprazole, which is less relevant
in overall population, might be of more interest in refractory one

57. When Should the PPI be Given?
15 – 30 minutes before meal
Before morning meal
Reduces acid secretion more than given in the evening
Does not affect nocturnal acid secretion
Before mid-day meal
More effective inhibition of nocturnal secretion
If single daily-dose Before breakfast or mid-day meals
If no response Divided doses: compliance problem
Increased dose (more reasonable)
Gomollo n F et al. Drugs 2005; 65 (Suppl 1) : 25 – 33.

58. PPI dose adjustment
• Renal failure No repercussion on PPI elimination
No need to adjust dosage
• Liver failure Half-life increases to 4 – 8 h (nl: 1 h)
Reduction of dosage
• Aged patients No dosage adjustment usually
Adjustment if hepatic or renal failure
is added to advanced age
Drugs 2005; 65 Suppl. 1

59. For how long?
Indication Duration
GERD Indefinite period of time or use on demand
HP eradication 7 – 10 – 14 days
Duodenal ulcer 4 wks – duration increased in refractory cases
Gastric ulcer 8 wks – duration increased in refractory cases
Bleeding PU IV PPIs for 72 hours (consensus)
Gastroprotection As long as patient requires NSAIDs or ASA
Dyspepsia Depend on symptomatic response
ZES Indefinite period of time

60. Which PPIs?
 Efficacy
Esomeprazole (40mg/d) slightly more effective
Useful in refractory ulcer
Useful in difficult GERD: extent of lesion – Barrett’s
 Interactions with other drugs
Less interaction in rabeprazole & especially pantoprazole
Clinical relevance probably minimal
Dose adjustment in AVK, benzodiazepines, phenytoin
 Cost considerations

61. Major metabolic pathways for various PPIs
De Argila CM. Drugs 2005; 65 (Suppl. 1) : 97 – 104.
Contribution of each isoenzyme represented by thickness of arrow
Rabeprazole: Important non-enzymatic metabolism
Pantoprazole sulfotransferase not saturable

62. PPI & clopidogrel co-therapy
 Evaluate risk of PU & GI bleeding in dual APT
 Administer PPI in patients at high risk
Administer PPI in all patients with dyspepsia
 Prefer pantoprazole or rabeprazole
Weak inhibitors of CYP2C19
Pantoprazole considered the first choice PPI
 Separate administration by 12 – 15 hours
Half life of PPI 1 – 2 h & clopidogrel 4 – 6 h
PPI before breakfast & clopidogrel after dinner
Lettino M. Eur J Intern Med 2010 (in press).

63. Mechanisms of suboptimal PPIs response
• Variable bioavailability of PPIs
• PPIs taken at times other than just before a meal
• Hypersecretors: uncommon
• Genetic variations in CYP 450 2C19 enzyme: rapid metabolism
• Eradication of H pylori: controversial
• PPI resistance despite normal blood levels of drug
Strongly suggesting genetic abnormality of proton pump
Ramakrishnan A. et al. Gastrointest Endoscopy Clin N Am 2003; 13 : 57 – 68.

64. Overprescribing PPIs
In a series of hospital inpatients in Michigan, USA
• On admission 20% of patients taking PPI
• During hospital stay Another 40% were prescribed PPI
Mostly for prophylaxis
• At discharge 50% of patients taking PPIs
90% of patients did not need PPIs
unless having GERD in the past
Ann Pharmacother 2006 ; 40 : 1261 – 6.
PPIs are clearly being overused

65. Overprescribing PPIs
• 2006 Expenditure on PPIs in England £425m
Expenditure on PPIs in the world £7bn
• 25-70% of pts taking PPIs have no appropriate indication
• Money spent unnecessarily on PPIs each year
England at least £100m
Worldwide at least £2bn
Bruzzi P. BMJ 2008 ; 336 : 2 – 3.

66. Conclusion
The lowest effective dose
of the cheapest drug
for the shortest possible time
Prescribing PPIs

67. Thank You