gerd ppn1112 wm

Management ofGastroesophageal Reflux Disease

GERD management primarily involves decreas-ing the acidic content of the stomach that is responsible for causing esophageal damage and improving the function of LES. Goals of GERD therapy include improving symptoms and quality of life, healing erosive esophagitis, and prevent-ing complications, such as esophageal stricture.

Epidemiology of GERDGERD is quite prevalent, with an estimated

44% of US adults experiencing heartburn—the principal symptom resulting from acid regurgi-tation—at least once a month.1 Many patients use over-the-counter (OTC) medications to self-treat heartburn symptoms. Although many patients suffer from occasional indigestion and get suffi-cient relief from these OTC medications, others have chronic attacks of heartburn that require further medical treatment.

The diagnosis of GERD is not always sim-ple or straightforward. Getting a patient’s com-plete medical history is the first step. If a patient has classic or typical symptoms of heartburn and regurgitation, with no additional compli-cations, then the diagnosis of GERD can be made with relatively high confidence. Although there is no gold standard for diagnosing GERD, because it involves alterations in acid secretion

and, therefore, pH, 24-hour pH monitoring with a probe is an accepted standard to establish or exclude the presence of the disease.2 Patients generally present to the outpatient pharmacy or clinic with symptoms of heartburn, dyspep-sia, or regurgitation. However, some patients may present with atypical or complicated signs and symptoms of GERD, such as asthma, chest pain, or chronic cough that may delay the diag-nosis of GERD (Table 1).3-5 Patients presenting with atypical or complicated symptoms should be referred to their health care provider immedi-ately for further assessment and should not treat themselves with OTC medications.

Pathophysiology of GERDGERD results from repetitive acid exposure to

the esophageal mucosa. The LES remains toni-cally contracted under normal resting conditions, but in cases of GERD it becomes “leaky,” allow-ing stomach contents to pass from the stomach into the esophagus. Any drug or disorder that increases LES relaxation or impairs reflexes fol-lowing normal LES relaxation may worsen GERD. Other pathophysiologic conditions such as hypothyroidism, diabetes mellitus, and asthma, as well as pregnancy, may worsen the disease. Lying in a supine position or bending over after

eating, or consuming a large meal can cause increased acid secretion and increased pressure on the LES and result in symptoms of GERD.

Acid Secretion and Its RegulationGastric acid secretion is stimulated by neu-

ronal (acetylcholine), paracrine (histamine), and endocrine (gastrin) mechanisms. The central nervous system (CNS) predominantly stimulates acid secretion by parietal cells through the action of acetylcholine on the enteric nervous system. CNS activation occurs in response to sight, smell, taste, or anticipation of food. Acetylcholine, released in response to CNS stimulation, causes the release of histamine from enterochromaffin-like cells. Histamine, in turn, acts as a paracrine regulator, causing acid secretion. The efficacy of histamine H2 receptor antagonists in blocking acid secretion clearly demonstrates the impor-tant role histamine plays in acid secretion. Gas-trin, the most potent stimulator of acid secretion, is released from antral cells via multiple mecha-nisms, including CNS activation, local distension, and triggering by certain chemical components of the gastric contents. On the other hand, gas-tric secretion is controlled via feedback regu-lation. Somatostatin, which is produced by the

Chronic gastroesophageal reflux

disease (GERD) results from the

dysfunction of the lower esophageal

sphincter (LES), which leads to frequent

exposure of the esophagus to gastric

contents, including substances such

as acid and pepsin that are harmful

to the esophageal epithelium.

M. CHANDRA SEKAR, RPH, PHDAssociate Professor

LORI ERNSTHAUSEN, PHARMD, BCPSAssistant Professor

College of PharmacyUniversity of FindlayFindlay, Ohio

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Pharmacy Practice News • November 2012

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antral cells, inhibits acid secretion by causing feedback inhibition of gas-trin release when the luminal pH falls below 3.0.

In addition to the somatostatin-based feedback regulation mecha-nism, another mechanism whereby the epithelial layer is protected from gastric acid is via prostaglan-din E2 and I2 stimulation of bicar-bonate release, which neutralizes gastric acid. The epithelial layer of the mucosa also is protected by insoluble gel that coats the mucous surface.

Nonpharmacologic Treatment All patients with GERD should

employ nonpharmacologic treat-ment options for the management of symptoms, regardless of wheth-er pharmacologic treatment is indi-cated. For patients coming to the clinic with their first experience of GERD, lifestyle changes should be employed for at least 2 weeks before scheduled acid-suppressing thera-py is recommended. Patients should be counseled to eat smaller meals and to avoid foods that may trigger symptoms of GERD (Table 2).6,7 The patient’s medication list also should be evaluated for any drugs that may cause relaxation of the LES or cause direct irritation of the stomach or esophageal mucosa. Patients expe-riencing symptoms at night may ele-vate the head of the bed or avoid eating meals before bedtime. Other nonpharmacologic lifestyle interven-tions that may improve GERD symp-toms include weight loss, smoking cessation, and avoiding or decreas-ing alcohol consumption.

Pharmacologic TreatmentPatients who do not experience

relief of their symptoms with life-style changes should continue with lifestyle modifications; however, scheduled acid-suppressing ther-apy with either antacids, H2 antag-onists, or proton pump inhibitors (PPIs) should be considered.8 The choice of whether to begin pharma-cotherapy with antacids, H2 antag-onists, or PPIs depends on patient preference, previous treatment suc-cess (if any), potential for drug interactions, cost, and convenience

(Table 3).9 Typically, OTC doses of H2 antagonists and PPIs are prescribed on a scheduled (once- or twice-dai-ly) basis for a 2-week trial. Antacids also may be used on a scheduled basis, as well, or in combination with H2 antagonists or PPIs for the treat-ment of breakthrough symptoms. Patients who do not achieve relief with scheduled OTC doses should continue therapy with either stan-dard-dose (prescription) H2 recep-tor antagonists for 6 to 12 weeks or PPIs for 4 to 8 weeks.

ANTACIDS

The mechanism of action of ant-acids is relatively straightforward and involves direct neutralization of acid via interaction with a base. Despite the simple mechanism, the appropriateness of any particu-lar antacid for the patient will be determined by the patient’s phys-iologic status, as well as personal taste and formulation preferences. Because patients usually obtain

their antacids OTC, pharmacists fre-quently are called on to consider dif-ferent patient-specific factors and provide counseling to help patients avoid further complications. Addi-tionally, they should advise patients to look for specific ingredients in their antacid preparations because manufacturers have started “brand-ing” antacid products with com-pletely different compositions with the same “name.” For example, 5 mL of Mylanta Supreme (McNeil) contains 400 mg of calcium car-bonate and 135 mg of magnesium hydroxide, but 5 mL of Mylanta Max-imum Strength (McNeil) contains 400 mg of aluminum hydroxide, 400 mg of magnesium hydroxide, and 40 mg of simethicone.

Although sodium bicarbonate is rapidly absorbed and effective at neutralizing acid, excess sodi-um resulting from its use could be risky for a patient with cardiac and renal failure. Additionally, belching produced by sodium bicarbonate

and calcium carbonate could be a problem in some patients. Mag-nesium- and aluminum-containing compounds provide a better neu-tralizing profile and greater sus-tained action; these agents often are used in combination and in lower doses to avoid the side effects of diarrhea (with magnesium) and constipation (with aluminum) asso-ciated with single-ingredient prod-ucts. However, in patients with renal insufficiency, increased absorp-tion of aluminum can contribute to osteoporosis, encephalopathy, and proximal myopathy, so products containing aluminum should be used with caution in this population.

Many antacid preparations also include simethicone, an antifoam-ing agent with a surfactant capa-bility that decreases foaming—by reducing the surface tension of gas bubbles so that larger bubbles can be eliminated easily. Like PPIs and H2 antagonists, antacids have a pH-altering property that may alter the absorption of certain drugs when they are given concomitantly. For example, pH affects the absorption of itraconazole, ketoconazole, glip-izide, glyburide, cefuroxime, digox-in, and indinavir. In contrast, drugs such as ciprofloxacin can chelate with aluminum and magnesium in the antacid.

The anionic polysaccharide algin-ic acid is capable of forming a “vis-cous gum” in the presence of water. Because of this, alginate has been used in antacid preparations such as Gaviscon (GlaxoSmithKline) to cre-ate a physical barrier that protects the epithelium from acid.

H2 RECEPTOR ANTAGONISTS

H2 receptor antagonists pre-vent acid secretion by competitive-ly inhibiting the binding of histamine to its receptor on the basolateral side of parietal cells. Because they predominantly suppress basal acid secretion, they are more effective for the treatment of peptic ulcer dis-ease than for the treatment of GERD.

The available H2 receptor antag-onists—cimetidine, famotidine, niza-tidine, and ranitidine—(Table 3) are less potent than PPIs; however, they do exert much faster onset of action than PPIs and produce 70%

Table 1. GERD Symptom Classification

Typical Symptoms Atypical Symptoms Complicated Symptoms

Heartburn

Hypersalivation

Regurgitation

Asthma

Chronic cough

Chronic sore throat

Dental erosions

Hoarseness

Laryngitis

Noncardiac chest pain

Anemia

Barrett’s esophagus

Bleeding

Choking

Dysphagia

Odynophagia

Weight loss

GERD, gastroesophageal reflux disease

Based on references 3-5.

Table 2. Foods and Drugs That Worsen GERD

Foods Drugs

Alcohol

Chocolate

Citrus fruits

Coffee

Fatty foods

Mint

Onions

Peppers

Spicy foods

Anticholinergics

Aspirin

Bisphosphonates

Caffeine

Corticosteroids

Dihydropyridine calcium channel blockers

Estrogen

Iron

Nitrates

NSAIDs

Potassium chloride

Progesterone

Tetracycline

GERD, gastroesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory drug

Based on references 6 and 7.

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inhibition following 24-hour admin-istration, thereby providing more rapid relief of symptoms. All 4 H2 antagonists are available as both prescription and OTC products. Three of them—cimetidine, raniti-dine, and famotidine—also are avail-able for IV and IM administration.

The H2 antagonists mainly dif-fer in their pharmacokinetics and potential for drug–drug interac-tions. They are rapidly absorbed following oral administration, and this absorption may be enhanced by food and decreased by antac-ids. Unlike PPIs, very small amounts of H2 antagonists are protein bound. The major excretion mechanism of H2 antagonists involves the kid-neys; thus they necessitate dosage adjustments in patients with renal, but not liver, dysfunction.

PPIS

PPIs are among the most potent inhibitors of acid secretion, inhibit-ing acid secretion by 80% to 95%. Their mechanism of action involves interaction with the activated

proton pump, leading to the pump’s inactivation. It takes several days of treatment with PPIs before the maximal inhibition of acid secre-tion is seen. Characteristics of the 6 available PPIs—dexlansoprazole (Dexilant, Takeda), esomeprazole (Nexium, AstraZeneca), lansopra-zole, omeprazole, pantoprazole, and rabeprazole (Aciphex, Eisai)—are shown in Table 3.

PPIs are prodrugs that get con-verted to an active drug under acid-ic conditions. This activation must occur in the canaliculi of the pari-etal cells. As food intake leads to acid secretion, and all the PPIs (except pantoprazole) inactivate only the active form of the proton pump, it is advisable to take PPIs 30 minutes before meals for maximum effect. It is very important for phar-macists to recognize and empha-size this difference to ensure an optimum therapeutic outcome. The only exception to this rule is panto-prazole, which is capable of inacti-vating the pump in both the basal and activated state.

To prevent the degradation of PPIs by acid in the gastric lumen, many formulations of PPIs are sup-plied in enteric-coated formulations. For patients who cannot swallow a tablet, orally disintegrating tablets and delayed-release suspensions are available.

PPIs are rapidly absorbed, high-ly protein-bound and extensive-ly metabolized by cytochrome P450 (CYP) enzymes. CYP2C19 and CYP3A4 are the 2 major CYP enzymes mainly involved in PPI metabolism. Asians are more likely to possess the “slow” metabolizing CYP2C19 genotype compared with Caucasians and blacks; this has been suggested to contribute to height-ened efficacy and toxicity of these agents among this ethnic group.8

Although no adjustment in the once-daily dosing is required for a patient with chronic renal failure, hepatic disease substantially reduc-es the clearance of esomeprazole and lansoprazole, necessitating dos-age adjustment.

PPIs have now been used for

more than 3 decades and have dem-onstrated a good safety profile. The most common side effects are nau-sea, abdominal pain, constipation, flatulence, and diarrhea. Other less common side effects include myopa-thy, arthralgias, headaches, and skin rashes. Caution should be exercised when any drug with pH-dependent absorption is to be administered to a patient receiving a concomitant PPI. A simple solution, if possible, would be to administer the drugs at least 4 hours apart.

Overall Treatment ApproachAs mentioned previously, all

patients should be counseled on lifestyle modifications to reduce the risk for and manage symptoms of GERD. Antacids, OTC H2 antagonists (taken up to twice daily), or PPIs (taken once daily) should be con-sidered for use as patient-directed therapy in those whose symptoms persist despite lifestyle changes (Figure).3,7 Patient-directed thera-py involves the use of antacids or

Table 3. Characteristics of Available GERD Treatments

Drug Usual Dosage Comments

H2 antagonists

Cimetidine 400a or 800a mg bid Greater interactions with CYP450 metabolizing pathway than other H2 antagonists

Famotidine 20 or 40 mg bid

Nizatidine 150a or 300a mg bid

Ranitidine 150 or 300 mg bid

PPIs

Dexlansoprazole (Dexilant, Takeda) 30 mg/d Interaction with antiretrovirals and methotrexate

Esomeprazole (Nexium, AstraZeneca) 20 or 40 mg/d Caution in patients with “slow metabolizer” of CYP450 pathway

Lansoprazole 30a or 60a mg/d Interaction with antiretrovirals and methotrexate

Omeprazole 20 or 40a mg/d Caution in patients with “slow metabolizer” of CYP450 pathway

Omeprazole with sodium bicarbonate 20 or 40a mg/d Caution in patients with “slow metabolizer” of CYP450 pathway

Pantoprazole 40 or 80a Less chance of interaction compared with other PPIs

Rabeprazole (Aciphex, Eisai) 20 or 40a mg/d Increases digoxin trough levels

bid, twice daily; CYP, cytochrome P450; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitora Unlabeled use.

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acid-suppressing therapy on an as-needed basis as symptoms arise or as GERD symptoms are anticipated. Many patients, however, still expe-rience symptoms despite patient-directed therapy and may require prescription-strength, acid-sup-pressing therapy with H2 antagonists or PPIs. Longer-term prescription-strength therapy should be titrat-ed to the lowest dose that provides control of the symptoms. Patients may use antacids for occasional breakthrough symptoms.10 Continu-ous daily administration of acid-sup-pressing therapy, particularly PPIs, has been shown to be more effective than patient-directed therapy; how-ever, patient-directed therapy may be appropriate for patients with less frequent heartburn or those who can identify trigger foods.11

Promotility agents and muco-sal protectants have been found to have limited roles in the treatment of GERD and are not routinely rec-ommended in the management of GERD. Likewise, the combination of acid-suppressant therapies (H2 antagonists and PPIs) is not rec-ommended and does not provide any additional benefit. Patients who continue to have symptoms despite optimal prescription-strength ther-apy should follow-up with their pre-scriber and may require further assessment, high-dose therapy, or surgery.12

ConclusionAppropriate management of

patients with GERD requires the use of lifestyle modifications along with pharmacologic agents such as ant-acids, H2 antagonists, and PPIs. Non-pharmacologic therapy is the basis of management for patients with

GERD, but in most cases therapeu-tic lifestyle changes do not con-trol symptoms. Pharmacists can serve to provide patient education on lifestyle interventions for symp-tom relief or assist patients with identifying triggers for their symp-toms. The choice among pharmaco-logic agents and length of therapy depends on various patient- and drug-specific factors and should be reassessed periodically to determine

any subsequent courses of therapy.

References

1. Sontag SJ. The medical management of refl ux esophagitis. Role of antacids and acid inhibition. Gastroenterol Clin North Am. 1990:19(3):683-712.

2. Johnsson F, Weywadt L, Solhaug JH, Hernqvist H, Bengtsson L. One-week omeprazole treatment in the diagnosis of gastroesophageal refl ux disease. Scand J Gastroenterol. 1998;33(1):15-20.

3. Zweber A, Berardi RR. Chapter 13. Heartburn and Dyspepsia. In: Krinsky DL, Berardi RR, Ferreri SP, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs An Interactive Approach to Self-Care, 17th ed. http://www.pharmacylibrary.com/resource/23. Accessed August 13, 2012.

4. Heidelbaugh JJ, Gill AS, Van Harrison R, Nostrant TT. Atypical presentations of gastroesophageal refl ex disease. Am Fam Physician. 2008;78(4):483-488.

5. Holtmann G, Bigard M, Malfertheiner P, Pounder R. Guidance on the use of over-the-counter proton pump inhibitors for the treatment of GERD. Int J Clin Pharm. 2011;33:493-500.

6. Dent J, El-Serag HB, Wallander M, Johansson S. Epidemiology of gastro-oesophageal refl ex disease: a systematic review. Gut. 2005;54(5):710-717.

7. Williams DB, Schade RR. Chapter 39. Gastroesophageal Refl ex Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. http://www.accesspharmacy.com/resourceToc.aspx?resourceID=669. Accessed August 13, 2012.

8. Dickson EJ, Stuart RC. Genetics of response to proton pump inhibitor therapy: clinical manifestations. Am J Pharmacogenomics. 2003;3(5):303-315.

9. Wallace JF, Sharkey KA. Goodman & Gilman. The Pharmacological Basis of Therapeutics, 12th ed. New York, NY: McGraw-Hill; 2001.

10. Kahrilas PJ. Clinical practice. Gastro–esophageal refl ux disease. N Engl J Med. 2008;359(16):1700-1707.

11. Ip S, Chung M, Moorthy D, et al. Comparative effectiveness of management strategies for gastroesophageal refl ux disease: update. Comparative Effectiveness Review No. 29. AHRQ Publication No. 11-EHC049-1. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=781. Accessed September 7, 2012.

12. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal refl ex disease. Am J Gastroenterol. 2005;100(1):190-200.

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Figure. Treatment approach for symptomatic GERD.

GERD, gastroesophageal reflux disease; H2RA, histamine-2 receptor antagonist; OTC, over-the-counter; PPI, proton pump inhibitor

Based on references 3 and 7.


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