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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%)
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 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)