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

2. 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

3. 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)

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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

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

13. 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

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

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

16. 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

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. Esophageal mucosal resistance: Alginic acid, Sucralfate
Esophageal clearance: Cisapride
LES pressure: MetoclopramideCisapride
Gastric emptying: Metoclopramide Cisapride
Gastric acid: Antacids H2RAs PPIs

26. 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

27. Drug Therapy - Antacids
Products: Magnesium salts, aluminum salts, calcium carbonate, and sodium bicarbonate
Dosing: Initially mEq prn (no more than 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 gm prn

28. 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

29. 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

30. 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

31. 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

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

33. 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

34. 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

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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

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

43. 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

44. 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

45. 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

46. 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.”

47. 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?

48. Questions???