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 Lower esophageal sphincter (LES) 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

Contributing Factors 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 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 OR proton 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 Cimetidine Famotidine Nizatidine Ranitidine Low dose (qd to bid) 200 mg 10 mg 75 mg Standard dose (bid) 400 mg 20 mg 150 mg High dose 400 mg qid or 800 mg bid 40 mg bid 150 mg qid

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 Timing 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 Typical symptoms are less frequent 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???