Drugs to Treat Gastric Acidity,

Peptic Ulcer Disease, and

Gastroesophageal Reflux Disease




Michael A. Pezzone, M.D., Ph.D.
Assistant Professor of Medicine and Pharmacology

University of Pittsburgh, Pittsburgh, Pennsylvania USA
Division of Gastroenterology, Hepatology and Nutrition and Department of
Pharmacology

Learning Objectives
1. Know the major classes of acid-suppressive
drugs and their mechanisms of action
2. Know the common side effects of acid-
suppressive drugs
3. Know the specific treatment of acid-peptic
disorders

Gastroesophageal Reflux
Disease (GERD)
A syndrome of symptomatic reflux of gastric contents
into the esophagus (i.e. heartburn)
Pathologic Reflux--reflux esophagitis or abnormal
ambulatory pH study
Functional Heartburn--non-erosive reflux disease

Gastric reflux contains a variety of esophageal irritants
Acid (2-3 liters per day)
Pepsin
Bile
Background


US
Population
Affected
Heartburn
Frequency
7% Daily
14% Weekly
15% Monthly
GERD Prevalence and Impact on QOL


Lifestyle modifications
Over-the-counter
medications
Head of bed elevation Antacids
Avoidance of tight-fitting clothes H
2
Receptor Antagonists (H
2
RAs)
Weight loss Proton Pump Inhibitor (PPI)
Restriction of alcohol
Elimination of smoking
Prescription medications
Dietary therapy Prokinetics
Refraining from lying down after
meals
H
2
RAs
Avoidance of evening snacks before
bedtime
PPIs
Surgery
GERD Treatment Options


Classes of Agents
1. Proton Pump Inhibitors
2. Histamine H
2
-Receptor Antagonists
3. Prostaglandin Analogs
4. Cytoprotectants
5. Antacids

1. Proton Pump Inhibitors
(PPIs)

PPIs
Most potent suppressors of acid secretion
Diminish basal and stimulated acid production
by 80-95%
24-48 hr effects on acid suppression
Acid-activated pro-drugs
PPIs
Irreversibly inhibit H
+
/K
+
ATPase function to:
Block gastric acid secretion
Decrease pepsin concentration
Increase gastric pH

Secretion of acid only resumes when new proton
pumps are deployed
Steady-state inhibition (affecting 70% of pumps)
may take 2-5 days
Typical dose is once daily (1 hr before breakfast)
PPI Pharmacology
Pro-drugs with pKa of approximately 4
Activated only when pH decreases below 4
Occurs only in parietal cell secretory canaliculi
Achieved only when parietal cell activation occurs
(after meals)
Most effective after a prolonged fast when large
amounts of active proton pumps are present (i.e.
breakfast)
Unstable at low pH (enteric coated or gelatin shell)
Available PPIs
Esomeprazole (Nexium)
Lansoprazole (Prevacid) (iv)
Omeprazole (Prilosec, Zegerid, generic, OTC)
Pantoprazole (Protonix) (iv)
Rabeprazole (Aciphex)

**All have equivalent efficacy at comparable doses
**Choice often based on prescription plan and co-pay
**Not necessarily first line therapy
**Pregnancy Category B (except omeprazole C)


PPI Structures
(substituted benzimidazoles)

Activation of Substituted
Benzimidazoles

H+/K+ATPase
**forms a disulfide bond with the cystine residues within the alpha subunit of the enzyme


80
1.6
PPI Metabolism
Rapidly absorbed
Highly protein bound
Extensively metabolized in the liver by the
P450 system (CYP2C19 and CYP3A4)
Sulfated metabolites are excreted in the
urine or feces
Hepatic disease reduces the clearance of
lansoprazole--reduce dose


Metabolized by hepatic CYPs
Common PPI Side Effects
Headache (2.9-6.9%) vs. Placebo (2.5-6.3%)
Diarrhea (3%) vs. Placebo (3.1%)
Abdominal pain (2.4-5.2%) vs. Placebo (3.1-3.3%)
Constipation (1.1-1.5%) vs. Placebo (0-0.8%)

B12 malabsorption reported with omeprazole
Drug-Drug Interactions
Warfarin (potentiated)
Esomeprazole
Lansoprazole
Omeprazole
Rabeprazole
Diazepam (potentiated)
Esomeprazole
Omeprazole
2. Histamine H
2
-Receptor
Antagonists (H
2
RAs)

H
2
RAs
Reversibly compete with histamine for binding
to H
2
receptors on the basolateral membrane
of parietal cells
Less potent than PPIs but still suppress acid
by 70% over 24 hrs
Predominantly inhibit basal acid suppression
(nocturnal)
Available OTC
Available H
2
RAs
Cimetidine (Tagamet)
Ranitidine (Zantac)
Famotidine (Pepcid) (iv)
Nizatidine (Axid)
**All exist in generic form
Pharmacokinetics
Rapidly absorbed after oral administration
Serum concentrations peak in 1-3 hr
Therapeutic levels maintained up to 12 hrs (Bid dose)
Small percentage is protein bound
10% to 35 % metabolized by the liver
Drugs and metabolites primarily excreted by kidneys
(**reduce doses in renal disease)
Development of tolerance (3 days)
Rebound response upon discontinuation
Common H
2
RA Side Effects
All less than 3%
Diarrhea
Headache
Drowsiness
Fatigue
Muscular pain
Constipation
Much less common
Confusion, delirium in the elderly
Associated with thrombocytopenia
Cimetidine anti-androgen effects
Drug-Drug Interactions
Avoided by not using cimetidine
Cimetidine inhibits CYPs

Pregnancy Category B
3. Prostaglandin Analogs:
Misoprostol

Protective Effects of
Prostaglandins
PGE
2
and PGI
2
synthesized by gastric mucosa
Acid-reducing effects
Bind to EP
3
receptors on parietal cells
Decrease acid production
Cytoprotective effects
Stimulation of mucin and bicarbonate
Increase mucosal blood flow
Contrast with NSAIDS which diminish prostaglandin
formation by inhibition of cycloxygenase and lead to
ulcer formation


Misoprostol: Cytotec
Synthetic analog of PGE
1
Enhanced potency
Increased oral bioavailability
Inhibit basal acid secretion (85-95%)
Inhibit stimulated acid secretion (75-85%)
Misoprostol Structure

PGE
1

Misoprostol
Pharmacokinetics
Rapidly absorbed
Rapidly de-esterfied to misoprostol acid--
the active metabolite
Therapeutic effect peaks at 60-90 minutes
Lasts 3 hours (qid dose required)
Free acid excreted mainly in urine
Side Effects
Diarrhea abdominal cramps as high as 30%
Begins within 2 weeks and often resolves
spontaneously in 1 week
Can exacerbate inflammatory bowel disease
Contraindicated during pregnancy (Cat x)
4. Sucralfate: Carafate

Sucralfate
Sulfated polysaccharide
Acid activated
Administered on an empty stomach 1 hr before meals
Undergoes cross-linking to produce a thick, viscous
polymer that adheres to epithelial cells and ulcer
craters for up to 6 hrs
Stimulates local prostaglandin synthesis
Binds bile acids


Sucralfate

Common Side Effects
Constipation (2%)
Aluminum toxicity
Avoid in renal failure
May impair absorption of other drugs
Thought to be safe during pregnancy (Cat B)
5. Antacids

Antacids
Sodium bicarbonate
CaCO3
Mg
2+
hydroxides
Al
3+
hydroxide

Antacids
Given orally 1-3 hrs after meals and bedtime
Single dose provides 120mEq neutralizing capacity-
-equivalent to one dose of an H
2
RA
Mg
+2
based preparations increase motility
Diarrhea
Al
+3
based preparations relax smooth muscle
Constipation
Ca
+2
based preparations release CO2
Belching, nausea, distension, and flatulence.
Common Side Effects
Aluminum toxicity with renal disease
Osteoporosis, enchephalopathy, myopathy
Hypercalcemia
Phosphate retention
Calcium precipitation in the kidney
Impair absorption of some drugs
Take 2 hrs before or after other drugs
Specific Treatments of Acid-
Peptic Disorders

Treatment of GERD
Goals
Resolution of symptoms (NERD)
Healing of esophagitis (pathologic GERD)


Healing rates
Drug 4wks 8wks
PPIs 80% 90%
H
2
RAs 50% 75%
GERD Therapy
(uncomplicated)
Empiric treatment with PPI or H
2
RA
Consider step-up therapy
EGD
Onset older than 40 yoa
Symptoms greater than 10 years
Not better with a PPI
Alarm symptoms such as dysphagia, weight
loss, melena
When stable, step-down therapy
Peptic Ulcer Disease (PUD)
Imbalance between mucosal defense factors and
aggravating factors (acid and pepsin)
Worldwide prevalence 10%
80-90% of ulcers related to H. pylori infection or
chronic NSAID use
Impaired production of somatostatin by D cells
Reduction of cytoprotective prostaglandins (PGE
2

and PGI
2
)
Healing Rates of PUD
PPIs 80-90 %
H2RAs, Misoprostol 60-75%

Invtravenous PPI is clearly the preferred
therapy in patients with acute bleeding
ulcers
H. Pylori Treatment
Reduces PUD Recurrence

10-20% vs. 55-70% (untreated)
Triple Therapy
PPI BID
Clarithromycin BID
Amoxicillin or Metronidazole
NSAID Ulcer Prophylaxis
Chronic NSAID users have a 2-4% risk of
developing symptomatic PUD
PPIs are more superior to H
2
RAs and
misoprostol in preventing PUD recurrence
Gastric ulcers 5-13% vs. 10-16%
Duodenal ulcers 0.5-3% vs. 4-10%
Heartburn in Pregnancy
LES decreases 33-50% during
2nd and 3rd trimesters--
progesterone mediated
EGD if needed (intractable
symptoms)
Therapy
1. Lifestyle modifications
2. Antacids
3. Sucralfate (Cat B)
4. H2RA (Cat B)
5. PPI (Cat B) except
omeprazole (Cat C)