Pharmacology of Acid

Neutralizing and
Suppressive Medications

Andrew DuPont, MD, MSPH

Assistant Professor
Division of Gastroenterology
 Overview

I. Physiology of acid secretion

II. Different agents for suppression of
gastric acid:- Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
III. Specific acid-peptic disorders
Gastric (oxyntic) gland

Shackelford’s Surgery of the Alimentary Tract,1995

Enterochromaffin-like (ECL) Cell

Stimulatory receptors:
- Catecholamine (β)
- Muscarinic (M3)
- Gastrin (CCKB)

Inhibitory receptors:
- Somatostatin (SSTR)
- Histamine (H3)
 ECL cell

Epinephrine
β● cAMP
M3
 Parietal Cell

Stimulatory receptors:
- Histamine (H2)
- Muscarinic (M3)
- Gastrin (CCKB)

Inhibitory receptor:
- Somatostatin
- Prostaglandin E2
 The parietal cell

CCKB
Gastrin

Ach Histamine
 Parietal Cell

Zuidema G: Shackelford’s Surgery of the Alimentary Tract, 4th ed. Philadelphia, WB Saunders, 1995
 The H+/K+-ATPase pump

- consists of 2 polypeptide subunits (α and β),

large cytoplasmic site with ATP binding region

- 15% of all pumps are inserted in the apical

membrane: most pumps are present in
cytoplasmic tubulovesicles

- Once stimulated, the vesicles fuse with the

membrane forming an apical meshwork of
intracellular canaliculi
Drawing of H+K+ATPase pump
Activation of the parietal cell

resting secreting

♦
CCKb
Mechanisms for Acid Secretion

Zuidema G: Shackelford’s Surgery of the Alimentary Tract, 4th ed. Philadelphia, WB Saunders, 1995
Mechanisms for stimulation of acid
secretion
 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
Anti-secretory agents: PPIs

M3
 Proton Pump Inhibitors (PPIs)
• omeprazole, esomeprazole, lansoprazole,
rabeprazole, pantoprazole.

∀ α-benzimidazoles

• Prodrugs

• Unstable at low pH

• Rapid absorption from duodenum, highly

protein-bound and metabolized by liver
(P450)
 PPI: kinetics

• Enter parietal cell from the blood, accumulate in

acid space where they are “activated”
(formation of sulfenamide)

• T1/2 = 1 hour

• Irreversibly inhibit the proton pump

• long duration of acid inhibition (>24 hours)

• Excreted in feces and urine

The chemical structure of
omeprazole
Omeprazole and the parietal cell
Mechanism of Action

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. 2006
 PPIs

• The activated form binds covalently

with sulfhydryl groups of cysteines
from the extracellular domain of the
H+K+ATPase pump
• Binding to cysteine 813 is essential
for acid inhibition
• Binding is irreversible and acid
secretion will only resume after new
pumps are inserted into the luminal
membrane
 PPI

• Take before meals!

Parietal cell stimulation will increase
translocation of pumps to the apical
membrane
• QD dosing: ~3 days before steady
state inhibition
• Inhibition will last 24-48 hrs
• Rebound hypersecretion does occur
after cessation of therapy
 PPIs: side-effects

• Diarrhea, headache, nausea

• ↑gastric pH
– ↓ketoconazole absorption
– ↑digoxin absorption
• Uncommon drug interactions with
omeprazole:
– Decreased clearance of benzodiazepines,
warfarin, phenytoin and disulfiram
• Rare: myopathy, arthralgias, rash
∀ ↓ B12 absorption
• Hypergastrinemia (5-10%)
 PPIs: side-effects (continued)

• ECL cell hyperplasia and gastric carcinoid

tumors
– reported in rats with long-term use of PPI
– in humans no evidence of ↑ gastric carcinoids

• Increased risk of enteric infection

– Clostridium difficile
– Traveler’s diarrhea

• No major teratogenic risk

– omeprazole is pregnancy class C
– all others class B
 PPIs & Bone Loss

• May increase bone loss and fracture

risk
– ↑gastric pH ↓calcium absorption
– Inhibition of osteoclastic vacuolar proton
pumps

• PPI use associated with a small

increase in hip fractures

Yang YX, et al. JAMA 2006 296:2947-53

 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
Anti-secretory agents: H2-blockers
 Histamine-2 receptor antagonist:
H2 blockers

• Inhibit by competitive binding at H2

receptor sites on the basolateral
membrane of the parietal cell

• H2 blockers: same clinical efficacy but

different side effect profile
Chemical structures of H2 receptor
antagonists
 H2 blockers: kinetics

• Absorbed in small intestine

• Unlike PPIs not highly protein-bound
• Extensive first-pass metabolism by liver
• Excreted by kidney:
– Moderate-severe RFReduce dose by
50%
– HD and PD only clear small amounts
• Near-complete inhibition of nocturnal and
basal acid secretion.
 H2 blockers: side effects

• Constipation, diarrhea, headache,

drowsiness, fatigue, muscular pain
• CNS: confusion, delirium, hallucinations,
slurred speech and headaches
• Thrombopenia
• Cimetidine (P-450): Drug interactions
gynaecomastia; galactorrhea
 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
Anti-secretory agents: misoprostol

•EP3
 Prostaglandin analogs:
Misoprostol

• GI mucosa: PGE2 and PGF2

• Paracrine action
• Misoprostol is a synthetic
analog of PGE1
 Misoprostol

• Bind to EP3 receptor on parietal cell

and inhibits acid secretion
• Also: ↑ mucin and bicarbonate
secretion
↑ mucosal blood flow
• Degree of acid inhibition is dose-
dependent
 Misoprostol: kinetics

• Rapidly absorbed
• First-pass metabolism to form
misoprostol acid (= active form)
• Acid suppression < 30 min; lasts ≈ 2
hrs
• T1/2 = 20- 40 minutes
• Excreted in the urine: renal dosing
not necessary
 Misoprostol: Side-effects

• Diarrhea! With or without abdominal

pain and cramps (30%)

• Contraindicated:
1 IBD
2 Pregnancy (class X)
 Misoprostol: indications

• Gastric ulcer prophylaxis in NSAID-

dependent patients

• 40% reduction rate in complications

 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
 Sucralfate

• Sulfated polysaccharides containing

Al(OH)3
• Extensive crosslinking and polymerization
(pH<4)
• Effects:
- Mechanical protection of epithelium
- Stimulates local PG synthesis
- Binds bile acids
- Inhibition of hydrolysis by pepsin
 Sucralfate: side-effects

• Constipation (2%)

• Inhibition of absorption other drugs

– take other medications 2 hours before.

• Contraindication: Renal failure

(because of aluminum)
 Sucralfate: Indications

• GERD and PUD

• Usually not used as first line drug

• Bile acid related reflux esophagitis

and/or gastritis
 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
 Antacids

• Seldom prescribed; used over

counter

• Alkalinize and neutralize gastric

contents

• Compounds are cleared rapidly from

stomach
 Antacids
• Products Al(OH)3 Mg(OH)2 CaCO3 Simethicone
(tabs/liquids)

• gelusil x x x
• maalox x x
• mylanta x x x
• riopan plus magaldrate x
• rolaids x
• tums ex x
• milk of magnesia x
 Antacids: side-effects

• Al, Mg, Na and Bicarbonate containing

antacids can pose a problem in renal
patients
• In renal insufficiency, Al can contribute to
osteoporosis, encephalopathy, proximal
myopathy, delayed gastric emptying,
constipation and interfere with absorption
of other drugs
 Milk-alkali syndrome

• Hypercalcemia
∀ ↓ PTH secretion
∀ ↑ Phosphate
• Ca2+ precipitation in kidneys/ CRI
 Overview

• Physiology of acid secretion

• Different agents for suppression of gastric
acid: - Proton Pump Inhibitors
- H2 Blockers
- Prostaglandin Analogs
- Sucralfate
- Antacids
• Specific acid-peptic disorders
Gastroesophageal reflux disease:
GERD

• 1:5 Americans: heartburn and/or

regurgitation at least once a week

• Complications:
- esophagitis/stricture
- chest pain
- laryngitis/asthma/chronic cough
- Barrett’s
 GERD

• Physicians should inquire about GERD

related symptoms
• Endoscopy is done to document whether
erosive esophagitis or Barrett’s metaplasia
are present
– Should be performed if GERD symptoms >5
years
• If either one is present patients will likely
need chronic life-long therapy with acid
suppressants or anti-reflux surgery
Barrett’s Esophagus
 GERD

Hiatal hernia Esophagitis

 Question

• What would you recommend for

this patient?

A Proton Pump Inhibitor

B H2 blocker
C Sucralfate
D Maalox prn symptoms
 GERD: acute symptoms

• PPIs > H2-blockers:

8 wk-healing rate: 90% vs 50-75%

• Dose determined upon symptom control

Reflux esophagitis
 GERD: maintenance

• GERD is chronic disease

• “step-down” approach:
↓ PPI or switch to H2-blocker
 NSAID related ulcers: treatment

• In general: use antisecretory drugs in

higher doses and for a longer duration

• PPIs > H2-blockers in

– both healing of active ulcers (90 vs 75%)
– and prophylaxis against recurrence of
gastric (5-13% vs 10-16%) and duodenal
ulcers (0.5-3% vs 4-10%) with continued
NSAID use
 Peptic Ulcer Disease
(Uncomplicated)

• PPIs > H2-blockers in symptom relief

and healing

• Maintenance: usually unnecessary if

H.Pylori eradicated
 Acid suppression in the
hospital setting
• Upper GI hemorrhage
- common reason for emergency care

- mortality rates: 3.5 -7.0 %

- 90%: EGD <24 hrs
- 25%: endoscopic hemostatic therapy
- 20% will rebleed
Elta. Yamada Textbook of Gastroenterology, 1999
 Why suppress acid secretion
in setting of upper GI
hemorrhage?

• Low pH impairs platelet function

• Pepsin can digest clots and its activity is
pH related

1 Han et al. Br J Haematol 26; 373-89, 1974

2 Patchett et al. Gut 30; 1704-7, 1989
3 Barkham et al. J Appl Physiol 6; 1-7, 1953
 Treatment with H2 blockers in
acute upper GI hemorrhage
• Widely used in the past

• Meta-analysis of 27 randomized trials suggests:

- Reduced rate of rebleeding by 10%
- Reduced need for surgery by 20%
- Reduced risk of death by 30%
for gastric ulcers only

• From Collins and Langman, NEJM 313; 660-666, 1985

Treatment with H2 blockers in
acute upper GI hemorrhage

• In a multicenter trial that compared iv

famotidine with placebo infusion in 1005
patients. No difference in
– the rate of recurrent bleeding
– need for transfusion or surgery
– mortality

Walt et al. Lancet 340; 1058-62, 1992

Treatment with PPI in acute
upper GI hemorrhage

• A comparison of omeprazole and

placebo for bleeding peptic ulcer
Khuroo MS, Yattoo GN, Javid G, Khan BA, Shah AA, Gulzar
GM, Sodi JS. NEJM 336; 1054-8, 1997

• Double-blind, placebo-controlled trial in

220 patients with duodenal and gastric
ulcers
 Treatment with PPI in acute
upper GI hemorrhage
omeprazole placebo
No of patients 110 110

Continued or
further bleeding 12/110 40/110 p<0.001

Subgroup analysis: significant reductions in recurrent

bleeding and surgery in patients with non-bleeding
visible vessels or adherent clots
Khuroo et al. NEJM 336; 1054-8, 1997
 Treatment with PPI in acute
upper GI hemorrhage
• Effect of intravenous omeprazole on
recurrent bleeding after endoscopic bleeding
treatment of bleeding peptic ulcers
Lau et al NEJM 343; 310-6, 2000

• Double-blind, placebo-controlled trial to

assess whether high dose intravenous PPI
after endoscopic treatment of bleeding ulcers
would reduce the rate of recurrent bleeding
 Treatment with PPI in acute
upper GI hemorrhage
• 240 patients with spurting or oozing
hemorrhage or non-bleeding visible vessels
• epinephrine and thermocoagulation
• omeprazole 80 mg iv bolus: 8 mg/hr/iv x72
hrs or placebo
• if rebleeding: repeat endoscopy
Lau et al NEJM 343; 310-6, 2000
 Treatment with PPI in acute
upper GI hemorrhage
IV omeprazole IV placebo

Recurrent bleeding < 3 days 5/120 24/120 p<0.001

Recurrent bleeding <30 days 8/120 27/120 p<0.001

Blood transfusion (units) 2.7+/-2.5 3.5+/-3.8 p=0.04

Mean hospital stay (days) 4 5 p=0.006

Lau et al NEJM 343; 310-6, 2000

 Acute upper GI bleeding
Conclusions

• Acute GI bleeding:
– Benefits of iv PPI therapy still under
investigation
– Used routinely if endoscopic therapy is
needed
– new studies are promising and suggest a
decreased rate of recurrent bleeding
 Case 1

• A 55 y.o. male, h.o. Billroth I for PUD,

complaints of chest pain and heartburn.
Endoscopy shows surgical changes and
frank bile reflux from the duodenum into
the remaining stomach and esophagus.
What would you recommend?
A Proton Pump Inhibitor
B H2 blocker
C Sucralfate
D Misoprostol
 Case 2

• A 75 y.o. female who takes a daily Motrin for

arthritis is diagnosed with 2 gastric ulcers on
endoscopy. You would recommend the
following EXCEPT:
• A An EGD 6 weeks after acid suppressive
therapy treatment
• B Discontinue Motrin and switch to COX-2
• C Discontinue Motrin and switch to a
different non-selective NSAID
• D Start a Proton Pump Inhibitor