Proton pump inhibitors (PPIs) like omeprazole irreversibly inhibit the gastric H+/K+-ATPase enzyme to reduce acid secretion. They are effective for treating acid-related disorders like GERD and peptic ulcers. PPIs have high bioavailability but require acidic conditions for activation. Common side effects include diarrhea and headache, while long term use may increase risks of infections, fractures, and nutrient deficiencies. Drug interactions are rare due to short half-lives, but some PPIs inhibit CYP2C19 and decrease clopidogrel effectiveness.

1. Proton pump
inhibitors (PPI)
Domina Petric, MD

2. Omeprazole, esomeprazole,
lansoprazole, dexlansoprazole,
rabeprazole and pantoprazole:
substituted benzimidazoles that
resemble H2 antagonists in
structure with different
mechanism of action.
Pharmacokinetics

3. Pharmacokinetics
• Omeprazole and lansoprazole are
racemic mixtures of R- and S-isomers.
• Esomeprazole is the S-isomer of
omeprazole and dexlansoprazole the R-
isomer of lansoprazole.
• All are available in oral formulations.
• Esomeprazole and pantoprazole are
also available in intravenous
formulations.

4. Pharmacokinetics
• PPIs are administered as inactive
prodrugs.
• Oral products are formulated for
delayed release as acid-
resistant, enteric-coated
capsules or tablets.

5. Pharmacokinetics
• After passing through the stomach
into the alkaline intestinal lumen, the
enteric coatings dissolve and the
prodrug is absorbed.
• For children or patients with
dysphagia or enteral feeding tubes,
capsules may be opened and the
microgranules mixed with juice.

6. Pharmacokinetics
• Lansoprazole is also available
as a tablet formulation that
disintegrates in the mouth.
• It may be mixed with water
and administered via oral
syringe or enteral tube.

7. Pharmacokinetics
• Omeprazole is also available as a
powder formulation (capsule or
packet) that contains sodium
bicarbonate (1100-1680 mg
NaHCO3: 304-460 mg of sodium) to
protect the naked drug from acid
degradation.

8. Pharmacokinetics
• When administered on an empty
stomach by mouth or enteral
tube, this immediate-release
suspension results in rapid
omeprazole absorption (within 30
minutes) and onset of acid
inhibition.

9. Pharmacokinetics
• PPIs are lipophilic weak
bases (pKa 4-5).
• After intestinal absorption
diffuse readily across lipid
membranes into acidified
compartment: the parietal cell
canaliculus.

10. Pharmacokinetics
• The prodrug rapidly becomes
protonated within the canaliculus
and is concentrated more than
1000-fold by Henderson-
Hasselbalch trapping.
• It rapidly undergoes a molecular
conversion to the active form.

11. Pharmacokinetics
• The active form is a reactive
thiophilic sulfenamide cation that
forms a covalent disulfide bond
with the H+/K+-ATPase.
• The active form irreversibly
inactivates the enzyme.

12. Pharmacokinetics
Drug pKa Bioavailability
(%)
t1/2 (h) Tmax (h) Usual dosage for
peptic ulcer or
GERD
Omeprazole 4 40-65 0,5-1,0 1-3 20-40 mg qd
Esomeprazole 4 >80 1,5 1,6 20-40 mg qd
Lansoprazole 4 >80 1,0-2,0 1,7 30 mg qd
Dexlansoprazole 4 1,0-2,0 5,0 30-60 mg qd
Pantoprazole 3,9 77 1,0-1,9 2,5-4,0 40 mg qd
Rabeprazole 5 52 1,0-2,0 3,1 20 mg qd

13. Pharmacokinetics
The bioavailability of all agents is
decreased approximately 50% by
food.
The drug should be administered
on an empty stomach, 1 hour
before meal.

14. Pharmacokinetics
• In a fasting state, only 10% of
proton pumps are actively
secreting acid and susceptible to
inhibition.
• That is why PPIs should be
administered 1 hour before a
meal (usually breakfast).

15. Pharmacokinetics
• The drugs have a short serum half-
life of about 1,5 hours.
• Acid inhibition lasts up to 24 hours
owing to the irreversible inactivation
of the proton pump.
• About 18 hours are required for
synthesis of new H+/K+-ATPase
pump molecules.

16. Pharmacokinetics
Up to 3-4 days of daily
medication are required before
the full acid-inhibiting potential is
reached.
After stopping the drug, it
takes 3-4 days for full acid
secretion to return.

17. Pharmacokinetics
• PPIs undergo rapid first-pass and
systemic hepatic metabolism and
have negligible renal clearance.
• Dose reduction is not needed for
patients with renal insufficiency
or mild to moderate liver disease.

18. Pharmacokinetics
• To provide maximal inhibition
during the first 24-48 hours of
treatment, the intravenous
formulations of esomeprazole
and pantoprazole must be given
as a continous infusion or as
repeated bolus injections.

19. Pharmacodynamics
PPIs inhibit both fasting and
meal-stimulated secretion.
In standard doses, PPIs inhibit
90-98% of 24-hour acid secretion.

20. CLINICAL USE

21. GERD
PPIs are the most effective agents for
the treatment of:
• nonerosive and erosive reflux
disease
• esophageal complications (peptic
stricture, Barrett´s esophagus)
• extraesophageal manifestations of
reflux disease

22. GERD
Once-daily dosing provides
effective symptom relief and tissue
healing in 85-90% of patients.
Up to 15% of patients require
twice-daily dosing.

23. GERD
• GERD symptoms recur in over 80%
of patients within 6 months after
discontinuation of a PPI.
• For patients with erosive esophagitis
or esophageal complications, long-
term daily maintenance therapy with
full or half-dose is needed.

24. Barrett´s esophagus
Massgeneral.org

25. GERD

26. GERD
Sustained acid suppression with twice-
daily PPIs for at least 3 months is used
to treat extraesophageal complications:
• asthma
• chronic cough
• laryngitis
• noncardiac chest pain

27. Peptic ulcer disease
All PPIs heal more
than 90% of
duodenal ulcers
within 4 weeks and
a similar
percentage of
gastric ulcers within
6-8 weeks.

28. H. pylori associated ulcers
Therapeutic goals are: heal the
ulcer and eradicate the
microorganism.
2 AB + PPI +/- bismuth salts!

29. H. pylori associated ulcers
PPIs promote eradication of H. pylori
through these mechanisms:
• direct antimicrobial properties
(minor)
• raising intragastric pH
• lowering the minimal inhibitory
concentrations of AB (antibiotics)

30. H. pylori associated ulcers
14-day regimen of triple therapy:
• PPI twice daily
• clarithromycin 500 mg twice daily
• amoxicillin 1 g twice daily or
metronidazole 500 mg twice daily
Bismuth quadruple therapy with
bismuth subcitrate.

31. H. pylori associated ulcers
After completion of triple
therapy, PPI should be
continued once daily for a
total of 4-6 weeks to ensure
complete ulcer healing.

32. H. pylori associated ulcers
Sequential treatment for 10 days:
• first 5 days PPI twice daily plus
amoxicillin 1 g twice daily
• other 5 days PPI twice daily plus
clarithromycin 500 mg twice daily
plus tinidazole 500 mg twice daily

33. NSAID-associated ulcers
• In patients with NSAID-
induced ulcers who require
continued NSAID therapy,
treatment with once or twice
daily PPI promotes ulcer
healing.

34. NSAID-associated ulcers
• Asymptomatic peptic ulceration
develops in 10-20% of people
taking frequent NSAIDs.
• Ulcer-related complications
(bleeding, perforation) develop in
1-2% of persons per year.

35. NSAID-associated ulcers
• PPIs taken once daily are
effective in reducing the
incidence of ulcers and ulcer
complications in patients
taking aspirin or other
NSAIDs.

36. Prevention of rebleeding from peptic ulcers
• Rebleeding of high-risk ulcers is
reduced significantly with PPIs
administered for 3-5 days either
as high-dose oral therapy
(omeprazole 40 mg orally twice
daily) or as a continuous
intravenous infusion.

37. Prevention of rebleeding from peptic ulcers
• Intragastric pH higher than 6 may
enhance coagulation and platelet
aggregation.
• Initial bolus administration of
esomeprazole or pantoprazole 80 mg
followed by constant infusion 8 mg/h
is recommended.

38. Prevention of stress-related mucosal bleeding
• Oral immediate-release omeprazole
formulation is administered by
nasogastric tube twice daily on the
first day, then once daily.
• For patients without a nasoenteric
tube or with significant ileus, iv. H2
antagonists are preferred.

39. Gastrinoma, other hypersecretion
• Isolated gastrinomas: surgical
resection.
• In patients with metastatic or
unresectable gastrinomas, massive
and hypersecretion results in peptic
ulceration, erosive esophagitis and
malabsorption.

40. Gastrinoma, other hypersecretion
• With PPIs, excellent acid suppression
can be achieved.
• Dosage is titrated to reduce basal
acid output to less than 5-10 mEq/h.
• Typical doses of omeprazole are
60-120 mg/day.

41. ADVERSE EFFECTS

42. General
• Diarrhea, headache and abdominal
pain are reported in 1-5% of
patients.
• Increasing cases of acute interstitial
nephritis have been reported.
• Safety during pregnancy has not
been established.

43. Nutrition
• Acid is important in releasing vitamin
B12 from food.
• A minor reduction in oral
cyanocobalamin absorption occurs
during PPIs therapy.
• Subnormal B12 levels may occur with
prolonged therapy.

44. Nutrition
Acid also promotes absorption
of food-bound minerals:
• non-heme iron
• insoluble calcium salts
• magnesium

45. Nutrition
PPIs may reduce calcium
absorption or inhibit osteoclast
function, especially in the case of
long term therapy:
• bone density control
• calcium supplements

46. Nutrition
Cases of severe, life-
threatening
hypomagnesemia with
secondary hypocalcemia
have been reported.

47. Respiratory and enteric infections
• Gastric acid is an important barrier to
colonization and infection of the
stomach and intestine from ingested
bacteria.
• There may be increased risk of both
comunity-acquired respiratory
infections and nosocomial
pneumonia.

48. Respiratory and enteric infections
• There is a 2 to 3-fold increased risk
for hospital and community acquired
Clostridium difficile infection.
• There is also a small increased risk
of other enteric infections:
Salmonella, Shigella, E. coli and
Campylobacter.

49. Increased serum gastrin
• Gastrin levels are regulated by
intragastric activity.
• Acid suppression alters normal
feedback inhibition so that
median serum gastrin levels rise
1,5 to 2-fold in patients taking
PPIs.

50. Increased serum gastrin
• Upon stopping the drug, the levels
normalize within 4 weeks.
• The rise in serum gastrin level may
stimulate hyperplasia of ECL and
parietal cells which may cause
transient rebound acid
hypersecretion.

51. Other
• Among patients infected with
H. pylori, long-term acid
suppression leads to
increased chronic
inflammation in the gastric
body and decreased
inflammation in the antrum.

52. Other
Long-term PPI therapy is associated
with the development of small benign
gastric fundic-gland polyps in a small
number of patients.

53. Drug interactions
Decreased gastric acidity may alter
absorption of drugs for which
intragastric acidity affects drug
bioavailability:
• ketoconazole, intraconazole
• digoxin
• atazanavir

54. Drug interactions
• All PPIs are metabolized by
hepatic P450 cytochromes,
including CYP2C19 and CP3A4.
• Because of the short half-lives of
PPIs, clinically significant drug
interactions are rare.

55. Drug interactions
• Omeprazole may inhibit the
metabolism of warfarin, diazepam
and phenytoin.
• Esomeprazole may decrease
metabolism of diazepam.
• Lansoprazole may enhance
clearance of theophylline.

56. Drug interactions
Rabeprazole and pantoprazole
have no significant drug
interactions!
They are appropirate choice, for
example, in patients taking
warfarin.

57. Drug interactions
• Clopidogrel is a prodrug that requires
activation by the hepatic P450
CYP2C19 isoenzyme.
• PPIs (especially omeprazole,
esomeprazole, lansoprazole and
dexlansoprazole) could reduce
clopidogrel activation and its
antiplatelet action.

58. Drug interactions
• Patients on clopidogrel should
take PPIs with minimal CYP2C19
inhibition (pantoprazole,
rabeprazole) if necessary:
increased risk of gastrointestinal
bleeding, chronic GERD or peptic
ulcer disease.

59. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• Massgeneral.org
• Homenaturalcures.com