Gastroesophageal Reflux Disease

Gastroesophageal Reflux Disease Scott Stolte, Pharm.D. Shenandoah University

Overview of GERD • Definition • Symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus • Classic symptom is frequent and persistent heartburn • 44 % of Americans experience heartburn at least once per month • 7 % have daily symptoms

Normal Function • Esophagus • Transports food from mouth to stomach through peristaltic contractions • Lower esophageal sphincter (LES) • Relaxes, on swallowing, to allow food to enter stomach and then contracts to prevent reflux • Normal to have some amount of reflux multiple times each day (transient relaxation of LES – not associated with swallowing)

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Pathogenesis • 3 lines of defense must be impaired for GERD to develop • LES barrier impairment • Relaxation of LES • Low resting LES pressure • Increased gastric pressure • Decreased clearance of refluxed materials from esophagus • Decreased esophageal mucosal resistance

Decrease LES pressure Chocolate Alcohol Fatty meals Coffee, cola, tea Garlic Onions Smoking Directly irritate the gastric mucosa Tomato-based products Coffee Spicy foods Citrus juices Meds: NSAIDS, aspirin, iron, KCl, alendronate Stimulate acid secretions Soda Beer Smoking Contributing Factors

Contributing Factors • Drugs that decrease LES pressure • Alpha-adrenergic agonists • Anti-cholinergic agents (e.g. TCA’s, antihistamines) • Beta-adrenergic agonists • Calcium channel antagonists (nifedipine most reduction) • Diazepam • Dopamine • Meperidine • Nitrates/Other vasodilators • Estrogens/progesterones (including oral contraceptives) • Prostaglandins • Theophylline

Lines of Defense • Clearance of refluxed materials from esophagus • Primary peristalsis from swallowing – increases salivary flow • Secondary peristalsis from esophageal distension • Gravitational effects • Esophageal mucosal resistance • Mucus production in esophagus • Bicarbonate movement from blood to mucosa

Pathogenesis • Amount of esophageal damage seen dependent on: • Composition of refluxed material • Which is worse: acid or alkaline refluxed material? • Volume of refluxed material • Length of contact time • Natural sensitivity of esophageal mucosa • Rate of gastric emptying

Typical Symptoms • Common symptoms most common when pH<4 • Heartburn • Belching and regurgitation • Hypersalivation • May be episodic or nocturnal • May be aggravated by meals and reclining position

Atypical Symptoms • Nonallergic asthma • Chronic cough • Hoarseness • Pharyngitis • Chest pain (mimics angina) • May be only symptoms – “omeprazole test”

Complications • Esophagitis • Esophageal strictures and ulcers • Hemorrhage • Perforation • Aspiration • Development of Barrett’s esophagus • Precipitation of an asthma attack

Barrett’s Esophagus • Highest prevalence in adult Caucasian males • Histologic change • Lower esophageal tissue begins to resemble the epithelium in the stomach lining • Predisposes to esophageal cancer (30-60x) and esophageal strictures (30-80% increased risk) • Odds ratio for development (compared with GERD < 1 yr.) • Patients with GERD 1-5 years – 3.0 • Patients with GERD > 10 years – 6.4 • More frequent, more severe, and longer-lasting the symptoms of reflux, the > the risk of cancer

Warning Signs If present, consider an endoscopy: • Dysphagia • Odynophagia • Bleeding • Unexplained weight loss • Choking • Chest pain

Diagnosis • Clinical symptoms and history • Presenting symptoms and associated risk factors • Give empiric therapy and look for improvement • Endoscopy if warning signs present

Refer • Chest pain • Heartburn while taking H2RAs or PPIs • Or heartburn that continues after 2 weeks of treatment • Nocturnal heartburn symptoms • Frequent heartburn for > 3 months • GI bleeding and other warning signs • Concurrent use of NSAIDS • Pregnant or nursing • Children < 12 years old

Therapy Goals • Alleviate or eliminate symptoms • Diminish the frequency of recurrence and duration of esophageal reflux • Promote healing – if mucosa is injured • Prevent complications

Therapy • Therapy is directed at: • Increasing LES pressure • Enhancing esophageal acid clearance • Improving gastric emptying • Protecting esophageal mucosa • Decreasing acidity of reflux • Decreasing gastric volume available to be refluxed

Treatment • Three phases in treatment • Phase I: Lifestyle changes – 2 weeks • Lifestyle modifications • Patient-directed therapy with OTC medications • Phase II: Pharmacologic intervention • Standard/high-dose antisecretory therapy • Phase III: Surgical intervention • Patients who fail pharmacologic treatment or have severe complications of GERD • LES positioned within the abdomen where it is under positive pressure

Treatment Selection • Mild intermittent heartburn (Phase I) • Treat with lifestyle changes plus antacids AND/OR low dose OTC H2-receptor antagonists (H2RA’s) as needed • Symptomatic relief of mild to moderate GERD (Phase II) • Treat with lifestyle changes plus standard doses of H2RA’s for 6-12 weeks ORproton pump inhibitors (PPI’s) for 4-8 weeks

Treatment Selection • Healing of erosive esophagitis or treatment of moderate to severe GERD (Phase II) • Lifestyle modifications plus PPI’s for 8-16 weeks OR high dose H2RA’s for 8-12 weeks • PPI’s preferred as initial choice due to more rapid symptom relief and higher rate of healing • May also add a prokinetic/promotility agent

Treatment Considerations • Prokinetic agents are an alternative to H2RA’s • Efficacy similar to prescription dose H2RA’s • Used as a single agent only in mild to moderate, nonerosive GERD • May be more expensive and use is limited by side effects

Treatment Considerations • Maintenance therapy may be needed • Large % of patients experience recurrence within 6-12 months after D’C of therapy • Goal is to control symptoms and prevent complications • May use antacids, PPIs or H2RAs • In patients with more severe symptoms, PPI most effective

Lifestyle Modifications • Elevate the head of the bed 6-8 inches • Decrease fat intake • Smoking cessation • Avoid recumbency for at least 3 hours post-prandial • Weight loss • Limit alcohol intake • Wear loose-fitting clothing • Avoidance of aggravating foods • These changes alone may not control symptoms

Esophageal mucosal resistance: Alginic acid, Sucralfate Esophageal clearance: Cisapride LES pressure: MetoclopramideCisapride Gastric emptying: Metoclopramide Cisapride Gastric acid: Antacids H2RAs PPIs http://www.gerd.com/intro/noframe/grossovw.htm

Drug Therapy - Antacids Antacids with or without alginic acid • Antacids increase LES pressure and do not promote esophageal healing • Neutralize gastric acid, causing alkalinization • Alginic acid (in Gaviscon) forms a highly viscous solution that floats on top of the gastric contents • Dose as needed – typical action – 1-3 hours • Not best choice for nocturnal symptoms because pH suppression cannot be maintained

Drug Therapy - Antacids • Products: Magnesium salts, aluminum salts, calcium carbonate, and sodium bicarbonate • Dosing: Initially 40-80 mEq prn (no more than 500-600 mEq per 24 hours) • Maalox/Mylanta 30 ml prn or PC & HS • Maalox TC/Mylanta II 15 ml prn or PC & HS • Gaviscon 2 tabs PC & HS • Tums 0.5-1 gm prn

Drug Therapy – H2RA’s H2RA’s • Mainstay of treatment for mild to moderate GERD • H2RA’s equally efficacious • Select based on pharmacokinetics, safety profile and cost • Timing • Give in divided doses for constant gastric acid suppression • May give at night if only nocturnal symptoms • Give before an activity that may result in reflux symptoms

Drug Therapy – H2RA’s

Drug Therapy – H2RA’s • Response to H2RA’s dependent upon: 1) Severity of disease 2) Duration of therapy 3) Dosage regimen used • Tolerance to effect develops

Drug Therapy - PPI’s Proton Pump Inhibitors • Used to treat moderate to severe GERD • More effective and faster healing than H2RA’s • May be used to treat esophagitis refractory to H2RA’s • All agents effective - choose based on cost • Prilosec released OTC 2003 • Use for heartburn that occurs ≥ 2 days/week • Label - Don’t use for more than 14 days

Drug Therapy - PPI’s • Standard dosing • Esomeprazole 20 mg qd • May 2006: FDA approved Nexium for adolescents 12-17 years for the short-term (up to 8 weeks) treatment of GERD • Lansoprazole 15-30 mg qd • Omeprazole 20 mg qd • Pantoprazole 40 mg qd • Rabeprazole 20 mg qd • Timing • Best is 30 minutes prior to breakfast

Drug Therapy - PPI’s • May give higher doses bid for • Patients with a partial response to standard therapy • Patients with breakthrough symptoms • Patients with severe esophageal dysmotility • Patients with Barrett’s esophagus • Always give second dose 30 minutes prior to evening meal

Drug Therapy - Prokinetics Prokinetic Agents -- MOA • Enhances motility of smooth muscle from esophagus through the proximal small bowel • Accelerates gastric emptying and transit of intestinal contents from duodenum to ileocecal valve

Drug Therapy - Prokinetics Prokinetic Agents • Results of therapy • Improved gastric emptying • Enhanced tone of the lower esophageal sphincter • Stimulated esophageal peristalsis (cisapride only)

Prokinetic Agents - Products Metoclopramide (Reglan) • Dopamine antagonist • Only use if motility dysfunction documented • Administer at least 30 minutes prior to meals • Dose - 10 to 15 mg AC and HS • Adverse Effects – limit use • diarrhea • CNS - drowsiness, restlessness, depression • extrapyramidal reactions – dystonia, motor restlessness, etc. • breast tenderness

Prokinetic Agents - Products Cisapride • Was removed from the market July 14, 2000 due to adverse cardiovascular effects (i.e. ventricular arrhythmias) • Available only through an investigational limited access program for patients who have failed all other treatment options

Drug Therapy – Mucosal Protectants • Sucralfate • Very limited value in treatment of GERD • Comparisons • Similar healing rate to H2RA in treatment of mild esophagitis • Less effective than H2RAs in refractory esophagitis • Only use in mildest form of GERD

Special Populations • Infants can experience a form of GERD • Postmeal regurgitation or small volume vomiting • Occurs due to a poorly functioning sphincter • Treatment • Supportive therapy • Diet adjustments – smaller, more frequent feedings; thickened feedings • Postural management • H2RA’s have been used (e.g. ranitidine 2 mg/kg) and antacids

Special Populations • Pregnancy • Common, due to decreased LES pressure and increased abdominal pressure • Nearly half of all pregnant women experience • Antacids other than sodium bicarbonate generally considered safe, but avoid chronic high doses

GERD in the Elderly • In the US, 20% report acid reflux • Worldwide, 3X prevalence in > 70 yo of patients younger than 39 yo • More likely to develop severe disease • More likely to be poorly diagnosed or underdiagnosed • Due to atypical symptoms • Always look for medication causes

GERD in the elderly • Symptoms • Dysphagia • Vomiting • Weight loss • Anemia • Anorexia • Typical symptoms are less frequent

GERD in the Elderly • Diagnosis should always include endoscopy • Prokinetic agents should be avoided • PPI’s are medications of choice for acute episodes and prevention of recurrence due to efficacy, safety, and tolerability • Step down approach is preferred – more clinically effective and more cost effective

PPIs in the Elderly • Decreased clearance with omeprazole, lansoprazole, rabeprazole • Little effect on clearance with pantoprazole • Dosage adjustments not necessary • Pantoprazole – lower affinity for CYP450

Counseling Questions • Before recommending a therapy, ask: • Duration and frequency of symptoms • Quality and timing of symptoms • Use of alcohol and tobacco • Dietary choices • Medications already tried to treat symptoms • Other disease states present and medications being used

Case Study • BT, a 45 year old male postal worker, complains of heartburn 3-4 times per month. The pain typically appears after meals. He has tried Tums with varying degrees of success. He would like something “more effective.”

Case Study • What questions should you ask BT first? • What would cause you to refer BT to a physician? • What type of GERD do you think BT has- mild, moderate or severe? • What treatment should you recommend?

Questions???

Gastroesophageal Reflux Disease