Heartburn and Dyspepsia

PATHOPHYSIOLOGY
Basic Upper GI Anatomy
Food travels along the gastrointestinal (GI tract) in the following fashion:

Mouth ! Esophagus ! Stomach ! Small Intestine

Three sphincters discussed in class control the movement of food within these different
compartments.

(1) The upper esophageal sphincter separates the mouth and the esophagus. It
opens whenever we are swallowing.
(2) The lower esophageal sphincter (LES) separates the esophagus and the
stomach. It opens to allow food into the stomach and remains closed
otherwise.
(3) The pyloric sphincter separates the stomach and the small intestine. It
opens to allow gastric juices and food digested by the stomach into the
small intestine for further absorption.

Food is brought into the stomach for three general purposes:

(1) Food storage
(2) Breakdown of food into liquid mixture by gastric juices
(3) Delivery of liquid mixture into the small intestine

Parietal cells within the stomach produce acid to aid in food digestion. Sodium
bicarbonate produced by mucosal cells neutralizes this acidic juice for protection.

Heartburn in the US
60% of the adult population experiences some type of GERD within 1 year.
20-30% will have weekly symptoms for as long as five years.
8-26% have symptoms 2-3% a week.
7-10% have daily symptoms.
30-50% of pregnant women experience heartburn during their pregnancies.
64.6 million prescriptions are written annually for GERD treatment.

Defining Heartburn
Heartburn is described as a warm discomfort, which begins in the lower chest and
travels to the neck. Patients may feel a burning sensation or pain in the lower chest.
This feeling is a result of stomach acid backing up into the esophagus.

There are various classifications of heartburn. Depending on the situation, a patients
heartburn can fit into more than one classification.

Simple heartburn: Infrequent heartburn that is mild, episodic, and typically can be
directly related to diet or lifestyle choices.

Frequent heartburn: Chronic or regular heartburn, which occurs at least 2 days every
week.
It is important to note that frequent heartburn, which persists for more than 3
months, is referred to as gastroesophageal reflux disease (GERD). If a patient
presents with frequent heartburn lasting for at least 3 months, he or she must be
referred to the M.D.
GERD is usually not relieved by antacids or any other OTC treatment. A diagnosis
cannot be made without an upper GI endoscopy and manometry.

Postprandial heartburn: Heartburn that occurs within 2 hours of eating a large meal or
other trigger food

Non-erosive gastroesophageal reflux disease (NERD): frequent and severe heartburn
without esophageal damage

Nocturnal heartburn: Heartburn that disturbs restful sleep. This occurs partly because
when a person lies flat, gravity no longer pulls down on the gastric juices, inviting the
juice towards the esophagus.

Defining Dyspepsia
Dyspepsia is a synonym for bad digestion.
It is defined as consistent or recurring discomfort in the upper abdomen. It is not
restricted to meal related symptoms. Dyspepsia often is associated with bloating,
belching, early satiety, and nausea.

The causes of dyspepsia are:
(1) Structural: Peptic ulcer disease or GERD damaging the lining of the
esophageal wall
(2) Functional/ idiopathic for 60% of patients

Contributing factors to heartburn and dyspepsia
- Weakened LES tone
o Sphincter is more readily opened
- Delayed stomach emptying
o Increases the gastric pressure, opening the LES
- Increased acid secretion
o Lowers the pH of the gastric juices, further exacerbates painful symptoms
heartburn/ dyspepsia
- Decreased salivation with increased age
o May cause stomach to work harder


Risk Factors
Diet Lifestyle
Chocolates
Fatty foods increase abdominal pressure
Spicy foods directly irritate the upper GI
tract
Spearmint/ peppermint
Garlic/ onions
Alcohol and caffeine lower the LES tone
Smoking
Stress
Exercise
Laying down within 3 hours after eating
Large meals
Tight fitting clothes
Obesity

Drugs (direct irritants) Drugs (lowers LES tone)
Bisphosphonates
Aspirin
NSAIDs
Iron
Potassium
Quinidine
Tetracycline
Estrogen
Morphine
Nitrates

- Prostaglandins protect the GI lining. NSAIDs inhibit prostaglandin production.
- Bisphosphonates are indicated for osteoporosis therapy.
- Iron and calcium interact.

Signs and Symptoms
Common Alarm [immediately refer to MD]
Burning sensation behind breast bone
Increased salivation
Burping/ belching
Regurgitation without nausea
Pain around epigastric area
Dysphagia (difficulty swallowing)
GI bleed (evidenced by dark stools)
Unexplained weight loss (at least 10% of
body weight)
Continuous nausea/ vomiting/ diarrhea

Heartburn Complications
If left untreated, heartburn can lead to a wide variety of other medical problems.
- Esophageal ulcers may led to short term and long term bleeding
- Esophageal strictures
- Trouble swallowing
- Cancer
- Barretts esophagus
- A decreased quality of life

Heartburn and Pregnancy
Heartburn occurs in 45-85% of women in the third trimester. For pregnancy-related
heartburn, antacids are safe as long as they are taken PRN and high doses are avoided.
Sodium bicarbonate containing antacids should be avoided, because the sodium
bicarbonate content can lead to fluid accumulation.

Tagamet (H2RA) has been shown to cross the placenta, but adverse effects to the child
have not been proven. Prilosec (PPI) crosses into breast milk, and its administration to
lactating women should only be considered if the benefits outweigh the risk. In general,
pregnant and lactating women should only take H2RAs and PPIs after M.D.
consultation.

Patients should seek medical attention if:
- Heartburn symptoms persist after two weeks of treatment with antacids or
H2RAs.
- Symptoms such as difficulty swallowing or persistent abdominal pain
occur.
- Chest pain occurs, particularly: tight, viselike pain or discomfort that
radiates the neck, shoulder, or left arm.

TREATMENT
Treatment of Heartburn
The purpose of treating heartburn and dyspepsia OTC is to achieve the following goals:
1. Relieve heartburn or prevent its recurrence
2. Relieve stomach pain/ discomfort
3. Prevent complications, such as ulcer formations
4. Improve the patients quality of life

Role of the Pharmacist
The pharmacist is responsible for assessing whether the patient is a candidate for self-
treatment, or whether the patient will need to be referred to an MD. The pharmacist
should recommend lifestyle changes that will improve the condition or prevent its
recurrence.

If appropriate, the pharmacist should recommend OTC medications based on the
specific patient, including: symptom presentation, lifestyle, cost issues, drug
interactions, and co-morbidities.

Primary Treatment Options
Once it has been assessed that the patient is experiencing simple heartburn and does
not need to be referred to a physician, there are three main drug classes which may
help treat the patient:
Antacids
Histamine-2 Receptor Antagonists (H2RAs)
Proton Pump Inhibitors (PPIs)

Remember, the pharmacist must always recommend lifestyle modifications.

Lifestyle Modifications
- Elevate the head of bed at least 6 inches before sleeping
- Eat no later than 3 hours before going to bed to allow adequate time for gastric
emptying
- Avoid foods that trigger heartburn
- Avoid lying down after meals
- Limit alcohol intake
- Smoking cessation
- Weight loss, if obese

Antacids
Antacids are used for temporary relief of mild and infrequent heartburn and dyspepsia.
It is not used for prevention.

Common antacid- containing products include Mylanta, Maalox, Milk of Magnesia,
Tums, Rolaids, Pepto Bismol, and Simethicone

Mechanism of action of antacids
(1) Increases LES tone to restore normal LES activity
(2) Neutralize stomach acid by acting as a pH buffer
All antacids contain at least one salt, which acts as a base, thereby
neutralizing gastric juices: sodium bicarbonate, calcium carbonate,
aluminum salts, and magnesium salts

Pharmacokinetics of antacids
Antacids begin working in less than 5 minutes.
On an empty stomach, they will work for 20- 40 minutes. When taken within one hour
of eating a meal, they will work for 2-3 hours.
Up to 10% of calcium will be systemically absorbed.
About 15-30% of magnesium and aluminum may be absorbed and renally excreted.

Potency of antacids
Sodium bicarbonate and magnesium salts dissolve more quickly in the stomach, but
have short durations of action.
Calcium and aluminum salts dissolve more slowly in the stomach, but have longer
durations of action.

Common side effects of antacids
Magnesium: Diarrhea without abdominal cramping
Aluminum: Constipation and hemorrhoids
Calcium carbonate: acid rebound and formation of kidney stones
Sodium bicarbonate: water retention

Antacids: Drug interactions
- Drugs, such as certain antibiotics, may chelate to the multivalent cations in the - -
antacids.
- Because antacids increase the pH of the gastric juices, drugs that require a low
intagastric pH for disintegration, ionization, or activation, may be affected
- Drugs with enteric coating may not uncoat due to the increased pH.
- Drugs that are affected by urine alkalinization.

Simethicone is an agent found in some antacids or by itself (Gas-X).

It is an anti-gas agent, which decreases bloating, abdominal pain, and discomfort.
It alters the surface tension of intestinal gas bubbles. Patients may experience
mild diarrhea and nausea while taking simethicone.

Tums is calcium carbonate.

Tums = 500 mg (200 mg calcium)
Tums EX = 750 mg (300 mg calcium)
Tums ultra = 1000 mg (400 mg calcium)

Patient education:
(1) Chew 1-2 tablets thoroughly up to every 2 hours
(2) Take with a full glass of water
(3) Take at least 1-2 hours before taking iron supplements
(4) Avoid alcohol, other antacids, caffeine, or other calcium supplements
(5) The maximum daily intake is 7000 mg of calcium.

Alka-Seltzer contains aspirin, sodium bicarbonate, and citric acid.

Sodium triggers the retention of water in the body, leading to potential fluid
overload. It may also lead to systemic alkalosis.

Patient education:
(1) Dissolve completely in water and wait until bubbles subside before
drinking

Bismuth subsalicylate is the active ingredient (525 mg/ 30ml) in Maalox Total Relief
and Pepto-Bismol.

Avoid in:
(1) Children below 16 years old, as they may be at risk for Reyes syndrome
(2) Pregnant or nursing mothers
(3) Patients with allergies to aspirin (acetylsalicylic acid) or salicylates

Patient Education
(1) Shake well
(2) Take 2 tablespoons every hour as needed with a full glass of water.
Maximum is 16 tablespoons.

Side Effects
Can cause temporary darkening of stool and tongue.

Patient Counseling Points of Antacids
- Take at onset of symptoms
o Taking it one hour after a meal will greatly increase the duration of action
- Consult label for ingredients, dosing
- See physician if symptoms persist for more than 2 weeks
- Inform them of the potential side effects
- Separate by 2 hours from interacting drugs
- Refrigerate liquids to improve taste

Histamine-2 Receptor Antagonists
H2RAs treat mild to moderate infrequent heartburn.
Like antacids, H2RA OTC therapy should not be used for longer than 2 weeks without
M.D. consultation.

OTC doses of H2RAs are lower than prescription doses.

A combined product (Pepcid Complete) contains both H2RAs and an antacid. It is used
for postprandial heartburn with patients who have not premedicated with an H2RA.

Mechanism of action of H2RAs
Histamine blockers work to prevent stomach release by inhibiting the proton pump.
However, it does not help to reduce the frequency of heartburn events.

The H-2 receptor typically binds histamine, resulting in a signaling cascade that
activates the proton pump to deliver protons to the lumen. H2RAs block the H-2
receptor, preventing the activation of this signaling cascade.

Pharmacokinetics
Onset of action: 30- 45 minutes
Duration of action: 6-10 hours (cimetidine shortest, famotidine longest)
Clearance: Combination of hepatic metabolism and renal elimination.
Food does not alter the bioavailability of H2RAs.
Tolerance develops in persons who take H2RAs long- term daily.

For best results, H2RAs should be taken one hour before symptoms are anticipated.

Potency
The effects of H2RA usually begin within 1 hour of administration and last for 6-10
hours.

There is a modest difference between non-prescription H2RAs, but they can be used
interchangeably. The exception to this generalization is cimetidine, which has the
shortest duration of action.

Only prescription strength H2RAs are proven and indicated for the healing of the
esophagus.

Precautions
Common Side effects
Headache
Drowsiness
General GI distress: Constipation, diarrhea, nausea, and abdominal pain

Dose adjustments are required in patients with renal impairment (Creatinine clearance
of less than 50 mL/min)

Drug Interactions
Because H2RAs increase the pH of the gastric environment, drugs that require a low
intragastric pH for disintegration, dissolution, or ionization (e.g. atazanavir, phenytoin,
ketoconazole) will decrease in levels.

Cimetidine inhibits CYP450 isozymes (3A4, 2D6, 1A2, 2C9), resulting in increased
levels of other drugs that are substrates.
The most significant drugs to take into consideration are warfarin, phenytoin,
and theophylline, as they all have narrow therapeutic windows.
Interaction potential of cimetidine and these other drugs are dose-related and
patient-specific.

Proton Pump Inhibitors (PPIs)
OTC PPIs are indicated to treat frequent heartburn in adult (over 18) patients with
symptoms 2 or more days per week.
If they experience heartburn 2 or more days per week for at least 3 months,
immediately refer them for M.D. consultation, because they may have GERD.

Chronic use (more than 2 weeks) is indicated to help heal an ulcer or for patients on a
course of NSAIDs, but only an M.D. may recommend this regimen.

Mechanism of action
PPIs bind irreversibly to the hydrogen- potassium ATPase in gastric parietal cells,
blocking the final step in gastric acid secretion. It is only effective in active pumps.

Pharmacokinetics
Onset of action: Symptom relief begins in 2-3 hours, but complete relief may take 1-4
days
Duration of action: 12-24 hours
Prilosec OTC, Nexium 24 hr, and Prevacid 24 hr contain multiple enteric-coated pellets
for delayed release.

Zegerid OTC is formulated with sodium bicarbonate for immediate release.

Precautions
Common Side Effects
Headache
Mild Rash
Dizziness
Cold Symptoms
Cough
General GI distress: Diarrhea, Nausea, and Vomiting, Stomach pain

Potential Long Term Complications (if taken for longer than 2 weeks)
Pneumonia
Chronic atrophic gastritis and gastric cancer
B12 malabsorption with chronic use of omeprazole
Hip fracture/ calcium malabsorption
Increased risk of C. diff infection
Acid rebound with chronic use

Drug Interactions
Increased bleeding with warfarin
Drugs that require an acidic environment for absorption (e.g. iron, tetracycline
antibiotics, digoxin)

2009 FDA warning for clopidogrel and omeprazole
Clopidogrel is a blood thinner. Proton pump inhibitors, specifically omeprazole, has ben
shown to inhibit CYP450 2C19, which is necessary for the activation of clopidrogel.

Cost comparisons of PPIs
Lansoprazole and omeprazole are roughly the same price, while esomeprazole is the
most expensive when sold as prescription medication.



SUMMARY OF KEY FACTS





KEY POINTS OF CLINICAL PRACTICE
- Heartburn and dyspepsia are common GI symptoms
- When heartburn is the dominant symptom, it is usually associated with GERD
- All patients may benefit from lifestyle modifications at any point of diagnosis
- Always be cognizant of alarm symptoms and refer patients immediately to an
M.D.
- Any patient self- treating longer than 14 days should be referred to an MD.

H2RAs
Brand Generic Dosing
Pepcid Famotidine 10-20 mg prn up to 2x/day
Zantac Ranitidine 75-150 mg
Axid Nizatidine 75 mg
Tagamet Cimetidine 200 mg
Pepcid Complete Famotidine + CaCO3 +
MgOH
1 tab prn

PPIs
Brand Generic Dosing
Prilosec Omeprazole 20 mg 1x/day
Nexium Esomeprazole 20 mg
Prevacid Lansoprazole 15 mg
Zegerid Omeprazole + NaHCO3 1 cap