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.

2.

3.

Know the major classes of acid-suppressive drugs and their mechanisms of action Know the common side effects of acidsuppressive drugs Know the specific treatment of acid-peptic disorders

Background

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 Acid (2-3 liters per day) Pepsin Bile

Gastric reflux contains a variety of esophageal irritants

GERD Prevalence and Impact on QOL

US Population Heartburn Affected Frequency 7% Daily

14%
15%

Weekly
Monthly

GERD Treatment Options

Lifestyle modifications
Head of bed elevation

Over-the-counter medications
Antacids

Avoidance of tight-fitting clothes

Weight loss Restriction of alcohol Elimination of smoking Dietary therapy Refraining from lying down after meals Avoidance of evening snacks before bedtime

H2 Receptor Antagonists (H2RAs)

Proton Pump Inhibitor (PPI)

Prescription medications
Prokinetics H2RAs PPIs

Surgery

Classes of Agents
1. 2. 3. 4. 5.

Proton Pump Inhibitors Histamine H2-Receptor Antagonists Prostaglandin Analogs Cytoprotectants 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

1.6 80

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%) Diarrhea (3%) Abdominal pain (2.4-5.2%) Constipation (1.1-1.5%)

vs. vs. vs. vs.

Placebo (2.5-6.3%) Placebo (3.1%) Placebo (3.1-3.3%) Placebo (0-0.8%)

B12 malabsorption reported with omeprazole

Drug-Drug Interactions

Warfarin (potentiated)
Esomeprazole Lansoprazole Omeprazole Rabeprazole

Diazepam (potentiated)
Esomeprazole Omeprazole

2. Histamine H2-Receptor Antagonists (H2RAs)

H2RAs
Reversibly compete with histamine for binding to H2 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 H2RAs

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 H2RA 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

PGE2 and PGI2 synthesized by gastric mucosa

Acid-reducing effects
Bind to EP3 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 PGE1

Enhanced potency Increased oral bioavailability

Inhibit basal acid secretion (85-95%) Inhibit stimulated acid secretion (75-85%)

Misoprostol Structure

Misoprostol

PGE1

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 Mg2+ hydroxides Al3+ hydroxide

Antacids

Given orally 1-3 hrs after meals and bedtime Single dose provides 120mEq neutralizing capacity-equivalent to one dose of an H2RA 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 AcidPeptic Disorders

Treatment of GERD

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

Drug PPIs H2RAs

Healing rates 4wks 8wks 80% 90% 50% 75%

GERD Therapy
(uncomplicated)

Empiric treatment with PPI or H2RA 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 (PGE2 and PGI2)

Healing Rates of PUD

PPIs H2RAs, Misoprostol

80-90 % 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 H2RAs 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)