Risk associated with PPI

1. HYPERACIDITY
The Main Problem in GI Disorders
By Aadil Sayyed
Medical Affairs
M-Pharm (Pharmacology)

2. WHAT ARE GI DISORDERS

3. OTHER CAUSES OF ACIDITY

4. COMMON SYMPTOMS IN GI PROBLEMS

5. MANAGEMENT OF GI DISORDERS
• Aluminum Hydroxide
• Magnesium Hydroxide
• Calcium Carbonate
Antacid
• Famotidine
• Ranitidine
• Cimetidine
H2 Blockers
• Omeprazole
• Pantoprazole
• Rabeprazole
Proton Pump
Inhibitors

6. ANTACID? H2 BLOCKER? PPI?

7. SELECTION IS DEPENDENT ON SAFETY &
EFFICACY
The Efficacy of these agents is well established.
Efficacy of PPI>H2 blocker>Antacids but safety of H2
blocker>Antacid>PPI

8. HOW H2 BLOCKERS ARE MORE SAFE THAN
PPIS?
PPI
Achlorhydria
malabsorption and
deficiencies of Ca &
Vit B12
bone loss
Malabsorption of Mg
Hypomagnesemia
Increased
Fracture Risk
In March 2011, the FDA released
a warning regarding low serum
magnesium levels associated
with long-term use of PPIs.
Health Canada issued an alert in April 2013 stating that patients with existing risk
factors for osteoporosis should be monitored closely and should also receive short-
term PPI therapy at the lowest effective dose
Increase in gastrin levels
PPIs are better inhibitors of
gastric acid secretion than H2
receptor blockers and are
therefore associated with
higher gastrin levels
Hypergastrinemia

9. PPIS ARE ASSOCIATED WITH INCREASED RISK OF
FRACTURE
 PPIs (but not H2RAs) are associated with an
increased risk of fracture1.
 35% increased risk of fracture,
 31% increased risk of hip fracture
 54% increased risk of vertebral fracture
 Moreover Indians already have high prevalence
(Up to 62%2) of Osteoporosis
1. ANNALS OF FAMILY MEDICINE ✦ WWW.ANNFAMMED.ORG ✦ VOL. 9, NO. 3 ✦ MAY/JUNE 2011
2. Int J Womens Health. 2015; 7: 841–850.

10. PPIS ARE ASSOCIATED WITH HYPOMAGNESEMIA
 More common in older patients (mean age 64.4
years)
FDA Suggests, patients who present with clinically significant
hypomagnesemia may require discontinuation of PPI therapy,
magnesium replacement via oral or IV methods, and treatment with
an alternative class of drugs for GI conditions such as an H2RAs
US Pharm. 2013;38(12):38-42
In 60% of adults the Magnesium intakes from food do not meet the estimated average
requirement
J Med Nutr Nutraceut [serial online] 2014 [cited 2017 Jul 26];3:66-72

11. PPIS ARE ASSOCIATED WITH CKD
 Kidney disease is a newer concern associated with PPI use.
 PPI therapy causes interstitial nephritis, which is a cause of acute kidney
damage.
 This acute kidney damage, coupled with the potential for
hypomagnesemia, can lead to an increased risk of chronic kidney damage
with PPI use.
A 2016 study by Lazarus et al. shows that, use of PPIs is independently associated with a 20%
– 50% higher risk of incident chronic kidney disease
Same study showed that the risk for CKD was lacking in patients prescribed
histamine-2 receptor antagonists, suggesting that the increased risk for
chronic kidney disease is specifically associated with PPI use and not
all acid-suppressive therapy
June 2016 Long-Term Care Updates

12. PPIS & B12 & IRON DEFICIENCY
 Vitamin B12 & Iron deficiency is another side effect
sometimes seen with acid-suppressive therapy.
 Gastric acid is needed for the dissociation of
vitamin B12 & Iron from food.
Prevalence of Vitamin B12 is 25% & Folate 51% in India
Indian J Med Res. 2011 Oct; 134(4): 432–439.
June 2016 Long-Term Care Updates

13. PPIS & RISK OF DEMENTIA
 Another new concern with long-term PPI use is the
development of dementia.
 Potential mechanisms for dementia development include
vitamin B12 deficiency, which has been associated with
cognitive decline, and the possible enhancement of amyloid
beta peptide levels in the brain.
 A recent study by Gomm et al. suggests that long-term PPI use
is associated with a 44% increased risk of dementia in
patients 75 years of age and older.
JAMA Neurol 2016;73(4):410-6.

14. PPIS ASSOCIATED WITH INCREASED RISK OF
INFECTION
PPI
Acid suppression
Raising PH
Prevents gastric Acid
from killing of
ingested C. difficile
CDI (C. Difficile Infection)
Gastric acid provides a host defense by killing ingested pathogens
Antimicrob. Agents Chemother.October 2009 vol. 53 no. 104133-4137
Clostridium difficile (C.
difficile or C. diff) is a gram-
positive, spore-forming,
anaerobic bacterium
transmitted through spores or
bacteria in stools or through
spores in the environment

15. PPIs
Delayed gastric emptying
Increased gastric contents
Increased bacterial load
Increased pressure on the lower esophageal sphincter
Retrograde movement of gastric contents up the esophagus
Increase the risk of subsequent aspiration of both the gastric contents and
the bacteria
CAP
World J Gastrointest Pharmacol Ther 2011 June 6; 2(3):17-26

16. PPIS ASSOCIATED WITH INCREASED RISK OF
INFECTION
 The 2013 American College of Gastroenterology (ACG)
guidelines warned about the risk of increased infections of C
difficile & CAP
 74% higher risk of developing C difficile infection.
75% of the patients with reported cases were over the age of 65 years.
Not only does long-term use of PPIs cause an increased incidence of C difficile, but
patients who received a PPI during treatment of C difficile were also 42% more likely to
have a recurrent infection after finishing therapy.
US Pharm. 2013;38(12):38-42
The 2013 ACG guidelines state that short-term PPI use may increase the risk of CAP.
*BMJ 2016;355:i6041

17. CONTD
 In 2012, Health Canada issued an advisory about the possible
association of PPI use and CDI.2 PPI prescribing
information must now include the precaution that a decrease in
stomach acid may increase the risk of gastrointestinal infections
such as Salmonella, Campylobacter, and C. diff.
 This warning reminds health professionals that PPIs should be
used at the lowest possible dose for the shortest possible
duration.

18. PPIS & GASTRIC MOTILITY
 PPIs can inhibit gastric motility and delay emptying rate
and, as a consequence, dyspeptic symptoms may actually
be worsened by PPI therapy or, alternatively, new
symptoms (especially postprandial fullness) may arise
during treatment.
 In this is the case, patients could be switched to the H2RAs,
which, in addition to their antisecretory activity, display a
cholinergic-like activity & have been shown to accelerate
gastric emptying.
 On the other hand, a Cochrane meta-analysis showed that
H2RAs are better than placebo in achieving symptom relief
in patients with Functional Dyspepsia.

19. SUMMARY
LIMITATION OF PPI
PPI Goes into Stomach
Causes reduction in acid levels
Reduces absorption of Nutrition
Increases Gastrin
Reduces B12 Absorption
Reduces Ca Absorption
Reduces Mg Absorption
Increases chn

20. SUMMARY: A POTENT ACID INHIBITOR MAY LEAD
TO POTENT ADVERSE EFFECT
 PPI are associated with number of serious adverse
effects
PPI
No more
choice of
drug
Increased risk of
fracture
Increased risk of
Hypergastrinemia
Increased risk
Dementia
HypomagnesemiaVitamin B12 & Iron
Deficiency
Increased risk of
Infection
Need of Safer option

21. H2 BLOCKERS
 H2-receptor antagonists are considered by many gastroenterologists to be the
'gold standard’.
 Comparable efficacy to PPIs.
 Safer option than PPIs.
 Not associated with fracture risk.
 Less effect on nutrition malabsorption than PPIs.
 1994, the American Academy of Pediatrics classified H2 blocker as
compatible with breast feeding & PPIs are contraindicated.
Aliment Pharmacol Ther. 1993;7 Suppl 2:35-40.
Aliment Pharmacol Ther. 2005;22(9):749-757.

22. LIMITATION OF H2 BLOCKER
 Slow Onset of Action.
 Rapid acid suppression is highly desirable in
hyperacidity.
 Hence onset of action should be fast.

23. FAMOTIDINE WITH CALCIUM
CARBONATE/MAGNESIUM HYDROXIDE
CHEWABLE TABLET
For Immediate & Sustained control of Acidity
A Safe & Effective combination

24. FAMOTIDINE + CALCIUM CARBONATE/MG
 Histamine H₂ receptor
antagonist that inhibits
stomach acid
production
 Onset of action is 90
min & duration is up to
12 hours
 Suppress 24-hour acid
secretion by 70%.
 Neutralizes Acid
 Rapid onset of action,
neutralizes 6.7 mmol
of acid in the first 30
minutes.
 Duration of action is
short up to 2 hours.
Aliment Pharmacol Ther. 2002 Jul;16(7):1317-26.
JAMA. 1996;275:1428-1431
Clinical Pharmacology And Rational Therapeutics (2Nd Edition)

25. RATIONALE OF COMBINATION
 Famotidine reduces the acid and pepsin production, as well as the volume
of basal, nocturnal and stimulated gastric secretion.
 Calcium carbonate is antacids and neutralize intraluminal acid on contact.
 Combination Combines the prolonged duration of effect of famotidine
with the rapid onset of action of antacids.
Parameters Famotidine1 Calcium carbonate1
Magnesium Hydroxide
Onset of action 90 minutes 30 minutes
Duration of action 10-12 Hours 60-120 minutes

26. BENEFITS OF ADDING ANTACID
 Calcium carbonate & Magnesium can neutralize
the pH in the range of 3.5 to 5 in just 15 minutes
which is ideal.
 Quick onset of action than PPI
 Less chances of acid rebound as it is combined
with H2 blocker.
Journal of institute of medicine Volume 20 Number 1 & 2 Jan-Mar/Apr-
Jun 1998

27. BENEFITS OF CHEWABLE TABLET
 Better bioavailability through bypassing disintegration (that increase dissolution)
 Improved patient acceptance (especially pediatric) through pleasant taste
 Patient convenience; need no water for swallowing
 Possible to use as a substitute for liquid dosage forms where rapid onset of
action is needed
 Absorption of drug is faster
 The large size of the dosage form is difficult to swallow. In such cases chewable
tablet offers advantages over it
 Effectiveness of therapeutic agent is improved by the reduction in size that occurs
during mastication of tablet before swallowing.
The Pharma Innovation Journal 2015; 4(5): 100-105

28. COMPOSITION
 Each Chewable Tablet Contains
 Famotidine 10 mg
 Magnesium hydroxide 165 mg
 Calcium carbonate 800 mg
 Dose
 One tablet to be chewed for the relief of symptoms.
 No more than two tablets to be taken in 24 hours

29. CLINICAL EFFICACY

30. EFFECT OF COMBINATION ON GASTRIC &
ESOPHAGEAL PH
 Conducted on 23 patients
 Results
 Administration of Combination of Famotidine with Antacid
with 60ml of water one hour after a high-fat evening meal
produced an increase of esophageal pH within 2
minutes.
 The increase of the gastric pH, above the increase
observed with placebo and antacid alone, remained for
12 hours.
Pepcidtwo tablet PI1

31. COMPARISON OF THE EFFECTS OF OVER-THE-
COUNTER FAMOTIDINE & CALCIUM CARBONATE
ANTACID ON POSTPRANDIAL GASTRIC ACID
 Participants. —Eighteen healthy volunteers (10 men
and 8 women) aged 25 to 62 years with normal gastric
acid secretion rates.
 Interventions. —The subjects received the
histamine2-receptor antagonist famotidine 10mg,
calcium carbonate antacid tablets 1000 mg, or placebo
medications 1 hour after a test meal.
 Two identical meals were taken 2.5 and 6.0 hours after
the medication was given.
(JAMA. 1996;275:1428-1431)2

32. MAIN OUTCOME MEASURES
 Intragastric pH was maintained at 4.0 by in vivo
intragastric titration with 0.3N sodium bicarbonate
for 10 hours (1 hour before and 9 hours after
medication).
 Reduction in sodium bicarbonate titrant use in the
2 treatment groups compared with titrant use with
placebo was reflective of acid secretion inhibited
by famotidine or acid neutralized by calcium
carbonate tablets.
(JAMA. 1996;275:1428-1431)

33. RESULTS
 When evaluated in increments of 30 minutes, calcium
carbonate had a rapid onset of action, neutralizing 6.7
mmol of acid in the first 30 minutes. However, its
duration of effect was only 60 minutes.
 Famotidine had a delayed onset of action compared with
antacid, beginning after 90 minutes.
 However, famotidine had a duration of effect of at least
540 minutes. At its peak effect, 210 minutes after
administration, famotidine reduced acid secretion by
7.3 mmol per 30 minutes.
(JAMA. 1996;275:1428-1431)

34. CONCLUSIONS
 Recommended over-the-counter doses of famotidine and
calcium carbonate tablets have different pharmacokinetic
profiles when taken in the postprandial period.
 The antacid has a rapid onset and short duration of action,
while the histamine2-receptor antagonist has a delayed
onset and a prolonged duration.
(JAMA. 1996;275:1428-1431)

35. CLINICAL STUDY ON THE INFLUENCE OF A FIXED-DOSE COMBINATION OF
FAMOTIDINE WITH CALCIUM CARBONATE AND MAGNESIUM HYDROXIDE ON THE
BIOAVAILABILITY OF FAMOTIDINE.
 A randomized, open-label, two-period, crossover study was
carried out on 12 healthy Chinese volunteers.
 Plasma concentration-time profiles of famotidine were similar with
the FDC formulation and common formulation. Confidence interval
(90% CI) for maximal concentration (C(max)) and area under the
curve (AUC(o-t)) of famotidine were 94.8-112.2% and 94.2-
112.3%, respectively.
 These findings suggest that calcium carbonate/magnesium
hydroxide antacids have no significant effects on famotidine
pharmacokinetics when they are administered together with
famotidine as an FDC formulation.
3 Arzneimittelforschung. 2008;58(11):581-4

36. SUMMARY
1. PPIs are associated malabsorption of Ca, Mg, Vitamin B12 & Iron.
2. We Indians are already highly deficient of these nutrients.
3. PPIs (But not H2 blockers) are associated with increased risk of fracture,
infection & CKD.
4. PPIs are also associated with hypergastrinemia.
5. PPIs may worsened dyspeptic symptoms as they inhibit gastric motility.
6. Unlike of PPIs, H2 blockers increases gastric motility.
7. H2 blockers are appeared as safer yet efficacious option than PPI.
8. H2 blockers are the gold standard in gastric disorders
9. Combination of H2 blockers+Antacid can offer very rapid (2 mins) &
prolonged duration of action.
10. Chewable tablet can offer extra advantage over normal tablet with better
compliance.
11. PPIs are contraindicated in lactation whereas H2 blockers & Antacids are
not.

37. GI PROBLEM?