Management of Gastroesophageal Reflux Disease_16

bout 36% of the population experience heartburn once a month, and up to 7% have heartburn ,\ daily. 1 Called gastroesophageal reflux, this motility disorder causes retrograde flow of stomach or duodenal contents into the esophagus and an increased residence time of acid. Gastroesophageal reflux disease (GERD) is any symptomatic condition or tissue damage that results from episodes of reflux. 2 Often treated by the primary care physician in the ambulatory setting, GERD is relatively benign and easily treated in some patients; however, others experience severe esophageal tissue damage, potentially resulting in esophageal ulcers, erosions, strictures, and motility disorders. 2,3 Treatment modalities are based on the severity of disease. Although several review articles of GERD and its treatment have been published, this review addresses the pharmacist's role in recognizing symptoms of GERD and provides guidelines for management and patient referral.4-7 In addition, this article summarizes efficacy studies of currently used treatment modalities and regimens. Pharmacists should focus on the following relevant practice information: atypical and typical signs of GERD, the mechanisms of action and efficacious dosage regimens for treating GERD, drug interactions, and adverse effects.

Pathophysiology , The pathophysiology of GERD is still not completely understood, but it can be mechanical or acid related. Gastroesophageal emptying relies on a functioning lower esophageal sphincter (LES) that prevents reflux of gastric contents back into the esophagus. Because the stomach has a higher pressure than the esophagus, a pressure gradient favors reflux into the esophagus. In healthy patients, the LES exerts a pressure more than 12 mm Hg above that of stomach pressure. LEs pressures of less than 12 mm Hg may result in reflux; in fact, LES pressures of less than 5 mm Hg are associated with severe GERD, but a linear relationship between reflux and LEg pressures does not appear to exist. 3 In healthy patients, the LES relaxes spontaneously to allow food to enter the stomach after swallowing. In patients with GERD, the LES relaxes more often and for longer periods of time, resulting in lengthened esophageal exposure to refluxed acid, which can Vol NS36, No. 1

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lead to mucosal injury.3,8 Thus, the degree of mucosal damage is related to the exposure time of gastric contents having a pH of less than 2 or greater than 7.9 The greater the exposure time, the more likely it is that irritation or erosion will occur. Impaired esophageal peristalsis, hiatal hernia, horizontal body position, and decreased salivation may also cause increased esophageal exposure to acid. 8,10-12 In addition to LES abnormalities, other mechanical. and metabolic causes of GERD exist. For example, up to 41% of patients with GERD have been shown to have delayed gastric emptying. 13 Delayed gastric emptying can lead to distention, increased volume, and intra-abdominal pressure, resulting in gastric reflux. A hiatal hernia, a protrusion of stomach tissue into the thoracic cavity through the esophageal hiatus,14 was once thOUght to be synonymous with reflux and GERD. Now considered to be an anatomical variant, a hiatal hernia can serve as an acid trap that promotes reflux during relaxation of the LES after swallowing, thus impairing esophageal clearance. Although the role of impaired mucosal defense is not well understood, it may also playa role in GERD.8 The primary initants found in the refluxate are gastric acid and pepsin. The esophageal mucosa is less resistant to gastric acid than to pepsin. However, patients with achlorhydria (absence of hydrochloric acid from gastric secretions) can develop esophagitis, which is thought to result from the action of bile acids or proteolytic enzymes.8 Finally, a nonfunctioning pyloric sphincter allows the reflux of bile acids and proteolytic enzymes into the stomach and subsequently into the esophagus, resulting in local initation and erosions. 3,8

. . • ' Pharmacists can help patients who experience mild '" GERD by rec0gnizing their symptoms, recommending , antacid therapy, and suggesting that they avoid certain foods and medications.

• Pharmacists should refer patients with more severe GE~D symptom~ to the physician, who can prescribe _-appropriate therapy to promote bealing and prevent serious tissue damage.

III

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Table 1

Dietary Factors Contributing to GERD

heartburn, bloating, regurgitation, belching, and nausea be initially treated with as-needed antacids as well as, therapy (see Table 4). Patients should be referred to physician if these signs or symptoms do not improve two days. Furthennore, the pharmacist should be some atypical GERD symptoms such as respiratory (e.g., coughing, hoarseness, and wheezing), chest pain, laryngeal or oropharyngeal symptoms. Dysphagia, loss, or unexplained anemia may indicate severe such atypical symptoms are exhibited, the patient should counseled to seek medical attention as soon as possible.

Diagnosis Risk Factors Certain medications and foods can decrease the LES pressure or have a direct irritant effect, thus causing reflux symptoms. Pharmacists must be aware of these drugs and foods to make appropriate assessments for patient self-treatment or physician referrals. Tables 1 and 2 list some of the foods and medications that can induce reflux symptoms and GERD. GERD is associated with other risk factors, including age. Infants have decreased gastric emptying and underdeveloped LES tone, thus increasing their risk for reflux. Gastric acid secretion decreases with age. However, because elderly patients tend to have decreased salivary production, esophageal peristalsis, and mucosal defense factors,15 they are still at risk for esophageal irritation and other symptoms of reflux. 16 In fact, one study using ambulatory pH monitoring reported heartburn in 14% of elderly ambulatory patients and abnonnal reflux in 20%.17 Cigarette smoking is another risk factor for GERD because nicotine decreases LES pressure. Decreased LES pressure caused by circulating progesterone and increased intra-abdominal pressure from the fetus 17 causes about 25% of pregnant women to experience heartburn daily and 52% to have heartbUf11 at least once a month. 1 Obesity can also predispose a patient to GERD because of a potential decrease in LES strength and an increase in intraabdorrtinal pressure. Finally, reflux and GERD symptoms are often clinical features of sclerodenna. 17

In addition to reviewing a patient's symptoms, the uses other procedures to diagnose GERD. Endoscopy or upper gastrointestinal (GI) series is used to image the gus and upper GI tract to rule out other diseases, such as cer or peptic ulcer disease, and to assess damage to the gus. For example, endoscopy detects the extent of damage, and biopsies detect epithelial damage. The or acid perfusion test has been widely used since 1 detennine if atypical symptoms (chest pain or oulmloruI1 symptoms) are caused by GERD. However, because of occurrence of false positive results in patients with ulcers or gastritis and the advent of 24-hour pH monitoring,

Symptoms Table 3 outlines common symptoms associated with GERD. Several of the signs and symptoms of GERD can be self-managed with pharmacist counseling. For example, Journal of the American Pharmaceutical Association

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Table 3

Signs and Symptoms of GERD Chest

GI Tract

Throat

Lungs

Miscellaneous

Chest pain

Belching

Hoarseness

Aspiration

GI blood loss

Dyspha'gia '

Bloating

Hypersalivation

Asthma

Hiccups

Heartburn

Early satiety

Lump in throat

Odyno~hag'i<:I

Nausea

Regurg itation GFR[) = ' $Jastr()~sophageal reflux disease; GI = gastrointestinal. Adapted fro.£n: R~ferehce 19; .used with permission. i:. ,~.,

: ~,.'

,~ ,

,!,-,-!<\,

"f,

.

•

of the Bernstein test is severely limited. 18 Twenty-four hour ambulatory pH monitoring can detect decreases in intraesophageal pH that may correspond to symptoms of GERD or reflux. To assess esophageal peristalsis before resorting to surgery, esophageal manometry is advised. 3,8,19

Management Therapeutic goals in management of GERD are multifold: relieve patient pain and symptoms, decrease frequency and duration of reflux, heal mucosal injury, and prevent complications and recurrence. 2 The pharmacist can play an integral role in monitoring therapy by questioning the patient each month about the achievement of desired outcomes. Treatment of GERD is usually divided into three phases of therapy. Phase I therapy, which incorporates lifestyle changes and antacid/alginic acid therapy4,14,15,20 (Table 4), helps alleviate symptoms in most patients with mild GERD. However, neither antacid nor alginic acid therapy promotes healing. If no symptomatic improvement occurs within two to three weeks, or if the patient's condition is severe, pharmacological measures of Phase II therapy should be initiated (fable 5). Medications lower the irritating and erosive factors in the refIuxate. Phase III therapy, surgery, is indicated in about 5% to 10% of patients with GERD.1°,14

neutralizing capacities, and some of their possible side effects. Although liquid and chewable tablets are most commonly used, medications are also available as tablets, chewing gum, powder, and lozenges. The pharmacist should counsel patients about the different antacid salts so that the best agent can be selected. Sodium bicarbonate is not recommended for long-term use because of its high sodium content and its potential for causing systemic alkalosis. Magnesium-aluminum antacid combinations are most commonly used because they minimize or counteract the diarrheal and constipating effects of the magnesium and aluminum salts, respectively. Because drug-drug interactions with antacids can occur (Table 7, page 22), pharmacists should chart regular antacid use on patient profiles and consider the potential for drug interactions. Antacids can bind to other drugs, rendering the bound drug insoluble. Antacids can also change gastric pH, which in turn Table 4

Phase I Therapy for GERD .. Lose weight (if over ideal body weight). ,

~ Decrease "or avoid certain foods (coffee, citrus fruits, chocolate). . • Decrease or stop smoking. , • Avoid alcohol. . ' Eat smaller meals. • Stay upright for two hours after meals. • Do not eat for three hours before sleeping.

Antacid Therapy Antacids neutralize gastric acid secreted by parietal cells in the stomach and bind to bile salts.21 By increasing gastric pH, antacids inhibit the proteolytic action of pepsin. Antacids may also exert a cytoprotective effect through increases in prostaglandin release, mucus production, and local blood SUpply. 21-24 Table 6 (page 21) lists the various antacid salts, their acidVol NS36, No. 1

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• Elevate head of bed. • Avoid tight clothing over abdominal area. • Use lozenges to increase saliva production. • Begin antacid/alginic acid therapy. GERD = gastroesophageal reflux disease. Sources: References 4, 14, 15, and 20.

journal of the American Pharmaceutical Association

alters the rate or extent of drug absorption. By increasing urinary pH, antacids may affect the urinary excretion rate of drugs that are weak acids. Although most drug interactions with antacids are not clinically Significant, phannacists should advise patients that when an antacid is taken concurrently with another medication, especially a drug with a narrow therapeutic index, the other medication should be taken two or more hours before the antacid, to achieve complete absorption of the drug. 25 The cost of antacid therapy depends on the antacid salt, the dosage fOnTI, and the frequency of administration. Third party insurance programs that cover the cost of prescription drugs often do not pay for over-the-counter (OTC) drugs such as antacids. Pharmacists are the ideal health care professionals for recommending the most appropriate antacid for a given patient. The higher acid-neutralizing power of liquid

antacids makes them the most cost-efficient formulati However, all antacids must be administered freque because of their short duration of action (45 to 60 minutes fasting patients). This duration increases to approximat two to three hours when the antacid is taken one hour after meal. 4 Although antacids provide symptomatic relief, t have not been shown to promote healing of damaged f in patients with GERD.24 Antacids are best used to pro · symptomatic relief in patients with mild-to-moderate GERI as adjuncts to more potent medications.

Alginic Acid Therapy Alginic acid (Gaviscon-Hoechst Marion Roussel), ill antacid therapy, is used for symptomatic relief. Although Table s

Phase II Therapy-Pharmacologic Measures for GERD Treatment

Nizatidine Onteprazo/e

Cost listed is the average wholesa'i e price for:: a 100 forhigh~st-strength product, ". less otherwise the average of three products' pf· " t

* Not indicated for GERD. Sources: References 5, 20, and 31.

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Table 6

Possible Side Effects of Antacid Therapy Antacid Salt

Trade Nania

Acid-Neutralizing Capacity*

Potential Adverse Effects

(Manufacturer) AlunJinunJ

Amphojel t (Wyeth-Ayerst)

10

Constipation, systemic aluminum toxicity, hypophosphatemia

Calc;unJ carbonate

Tums E-X Extra Strength (SmithKline Beecham)

15

Constipation, hypercalcemia, acid rebound

Magnes;unJ

Maox (Kenneth A. Manre)

21

Diarrhea, hypermagnesemia, magnesium cardiotoxicity

Sod;unJ bicarbonate

Various

t

'\"

n.a.*

Sodium overload, systemic alkalosis, milk-alkali syndrome

' .

* Acid~ neutrali~~ng capacity per tablet, capsule, or 5 mL of suspension is defined as the mEq of hydrochloric acid required to keep

the antacid slJspe!1sion at a pH of 3.0 for two hours. t

.

Liquid dosage formulation.

*Acid-neutralizing capacity not available for this formulation. Source~: References ~, 4,26, and 31.

agent is not an antacid, alginic acid preparations usually contain small quantities of antacid to convert alginic acid to sodium alginate, a viscous foam that floats on the surface of the gastric contents. If reflux occurs, the sodium alginate provides a barrier that prevents exposure of the esophageal mucosa to acid. Thus, the amount of antacid in alginic acid preparations is not sufficient to alter gastric pH. 4 Alginic acid is available as oral or chewable tablets or a suspension. Alginic acid preparations are considered to be at least as effective as antacids for relieving symptoms, but like antacids, they do not promote healing in patients with GERD. 4 ,26

Histarnine2 -Receptor Antagonists Cimetidine (Tagamet-SmithKline Beecham), ranitidine (Zantac-Glaxo Wellcome), famotidine (Pepcid-Merck), and nizatidine (Axid-Lilly) are the four histamine 2 (H 2)receptor antagonists currently available in the United States. Hfreceptor antagonists inhibit binding of histamine to H2 receptors in the parietal cells of the stomach, resulting in decreased gastric acid secretion. The pharmacokinetic properties of various H2-receptor antagonists are similar. Bioavailability ranges from 30% with cimetidine to 75% to 100% with nizatidine. 27 Serum protein binding of all four agents is relatively low (for example, 15% to 20% for cimetidine, ranitidine, and famotidine, and up to 35% for nizatidine). Their elimination half-lives range from one to four hours. 27 Advanced age and liver impairment lower cimetidine clearance but appear to have little effect on the other H2 -receptor antagonists. Because all four drugs are Vol NS36, No. 1

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renally excreted, dosage reductions are recommended in patients with renal impairment. Overall, the H2-receptor antagonists cause few serious adverse effects. In clinical trials, diarrhea, headache, drowsiness, fatigue, muscle pain, and constipation were reported in less than 3% of patients. 27 Because of cimetidine's structure, it has a greater ability to cross the blood-brain barrier, potentially causing central nervous system (CNS) effects, especially in elderly patients. Although cimetidine and ranitidine can increase serum prolactin levels, which causes breast swelling and galactorrhea in women and gynecomastia in men, famotidine and nizatidine do not. Impotence has been implicated with cimetidine therapy; however, cimetidine-induced impotence usually reverses within one month after switching to ranitidine. 27 Cimetidine has also caused loss of libido. Finally, although elevations in serum levels of the aminotransferase enzymes have been shown and are usually reversible, hepatitis has rarely occurred. 27 ,28 The H2-receptor antagonists may interact with other drugs or inhibit their metabolism. The H2-receptor antagonists can increase gastric pH, thus decreasing the absorption of drugs dependent on an acidic environment (Table 7). H2-receptor antagonists also inhibit cytochrome P-4S0 enzymes, which are involved in the metabolism of other drugs. Although cimetidine is the most potent inhibitor of cytochrome P-450, ranitidine binds receptors 5 to 10 times less than cimetidine does; famotidine and nizatidine do not bind significantly.27 Serum levels of medications metabolized in the liver may rise when H2-receptor antagonists are taken concomitantly; this effect is seen particularly with cimetidine. If an ~~receptor antagonist

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}ownal of the American Phannaceutical Association

is discontinued, serum levels of medications metabolized in the liver can decrease because their metabolism is no longer inhibited. H 2-receptor antagonists may also inhibit renal tubular secretion of certain drugs (e.g., procainamide and triamterene). Dosing of the H2-receptor antagonists for GERD depends on the individual patient and the severity of the disease. All of the H2-receptor antagonists have been approved by the Food and Drug Administration (FDA) for treatment of GERD. Generally, clinicians initiate GERD therapy with standard duodenal ulcer treatment doses of H 2-receptor antagonists, but in most cases, much higher doses are required to treat and manage GERD symptoms. Studies show that high-dose or highfrequency H2-receptor antagonist therapy relieves reflux symptoms in about 75% of patients. 8 However, healing may be inadequate (about 33%) using standard doses for peptic

journal of the American Pharmaceutical Association

ulcer disease treatment. 8 For example, patients given dine 150 mg twice a day for erosive or ulcerative esolohai!il showed healing rates of 31 % and 50% after four and weeks, respectively.29 Healing was defmed as malCr()SC()oitJ ly complete epithelialization of all erosive or ule lesions of the esophagus. Comparing a high dose of 300 mg twice a day with a standard dose of nizatidine 300 at bedtime and with a placebo showed six-week healing of 40%, 30%, and 26%, respectively. 27 Because H2-receptor antagonist therapy-even at twice standard dose for duodenal ulcers-is unsuccessful in mately 50% of patients with GERD,4 many studies have ed high-dose or high-frequency H2-receptor antagonist In one study comparing ranitidine doses of 300 mg four tima day with doses of 150 mg twice a day, complete healing

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vol. NS36,

esophageal ulcers or erosions occurred in 63% and 75% of patients given high doses after four and eight weeks, respectively, whereas 29"/0 and 54% of patients given standard doses were healed. 2o ,27 In addition, some patients have required up to 3,600 mg of ranitidine per day to promote healing.30 Although H2-receptor antagonists are considered safe and well tolerated at moderate doses, possible side effects at high doses have not been investigated. Therefore, the lowest effective dose should always be used. Hz-receptor antagonist therapy for GERD must be more frequent than that for peptic ulcer disease-at least twice a day or more often. Split-dose therapy inhibits both daytime and nocturnal acid secretion, thereby relieving symptoms, promoting healing, and improving overall patient outcomes. 5 Unlike patients with duodenal or gastric ulcers, those with GERD frequently require prolonged doses of H2-receptor antagonist therapy. 2 Although H2-receptor antagonist therapy is relatively safe, relieves painful symptoms, and promotes healing of erosions or ulcers, it can be expensive, especially if given frequently at the higher doses. Healing efficacy varies from patient to patient. Thus, H2-receptor antagonists should be reserved for patients with mild GERD who do not respond to more costeffective antacid therapy or for patients with moderate-tosevere GERD.

Omeprazole Omeprazole (prilosec-Merck) is a substituted benzimidazole that suppresses gastric acid secretion by irreversibly and noncompetitively inhibiting the acid proton pump of the parietal cell. Acid suppression is profound; a single dose suppresses acid secretion by more than 90% for 24 hours. 2o Maximal antisecretory activity and omeprazole plasma levels occur about two hours after an oral dose. Omeprazole has a high firstpass effect; bioavailability is only about 30% to 40% of an oral dose, and protein binding is high (about 95%).31 Almost 80% of the drug is eliminated renally as six metabolites, which have little or no antisecretory activity. The remaining drug is excreted through the biliary system. Although the elimination half-life is about two to three hours,32 the antisecretory action of omeprazole can last up to 72 hours, because of prolonged protonpump binding,31 Dosage adjustments are not necessary in patients with renal impairment. Omeprazole has no effect on renal tubular handling of acid or on renal electrolyte excretion.32 Although dosage adjustment is unnecessary in patients with hepatic impairment, liver disease increases omeprazole's bioavailability and decreases its clearance. Nevertheless, these patients should be monitored for adverse effects. A concern with widespread use of omeprazole is its longterm safety profIle. Two-year studies in rats indicated a doserelated increase in gastric carcinoids. However, data from patients with Zolinger-Ellison syndrome who received omeprazole for up to four years revealed no detectable carciVol NS36, No.1 January 1996

noid tumors. 33,34 Adverse effects of omeprazole are relatively minimal. Headache is the most frequent complaint, occurring in approximately 7% of patients. Diarrhea, abdominal pain, nausea, upper respiratory infection, vomiting, dizziness, and rash have been reported in less than 4% of patients.31 Because omeprazole inhibits the isoenzyme H-C of the P-450 enzyme system, it may interact with other drugs metabolized by this route (fable 7, page 22). In addition, a catatonic reaction was reported in a patient receiving disulftram (Antabuse-Wyeth-Ayerst) and omeprazoleY The clinical significance of these interactions has not been deteffilined, but close monitoring is recommended. Because omeprazole increases gastric pH, serum concentrations of drugs that require an acidic environment for absorption can decline. 31 ,32 Currently, FDA has approved omeprazole for severe erosive esophagitis and for poorly responsive symptomatic GERD, including cases that respond inadequately to Hzreceptor antagonist therapy. Studies comparing omeprazole once daily with H2-receptor antagonists or placebo have been favorable. In a study of 230 patients with reflux esophagitis, 74% of patients given omeprazole 20 mg/day and 75% of patients given 40 mg/day were healed after eight weeks, compared with 14% of patients receiving placebo.35 Metaanalysis of trials comparing omeprazole (20 mg or 40 mg/ day) with ranitidine (300 mg/day) showed significantly better healing rates after four and eight weeks for patients taking omeprazole.35 Omeprazole has been shown to be effective in patients with resistant esophagitis whose disease was not healed by H 2-receptor antagonist therapy. Ninety-eight patients whose esophagitis continued after three months or more of ranitidine or cimetidine therapy were randomized to receive either omeprazole 40 mg/day or ranitidine 300 mg twice a day. After 12 weeks, 46 of 51 patients (90%) reCeiving omeprazole experienced healing, compared with 22 of 47 patients (47%) taking ranitidine (p < 0.001).36 Bardhan et alY studied 45 patients whose esophagitis was refractory despite at least three months of either cimetidine 3.2 grams/day or ranitidine 900 mg/day. These patients were treated in an open trial with omeprazole 40 mg/day for up to eight weeks. After four and eight weeks, healing occurred in 73% and 91 % of patients, respectively. 35 Dosing and length of therapy with omeprazole are somewhat controversial. Currently, only 20 mg/day is FDA approved for GERD therapy. However, higher doses have been used for patients with refractory GERD. ·~8 The manufacturer recommends that an initial dose of omeprazole 20 mg/ day be used for at least four weeks before increasing the dose to 40 mg/day.s Length of treatment is usually four to eight weeks, with an additional four weeks if healing has not occurred. Maintenance therapy with omeprazole is effective, but the appearance of gastric carcinoids in rats given high doses over long periods of time has raised concern. Omeprazole, an acid labile compound, is formulated as

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enteric-coated granules. The intact capsules should not be crushed or mixed with food or enteral feedings.5 However, omeprazole granules have been mixed with acidic fruit juices for patients who cannot swallow capsules or require administration through a nasogastric tube. 4 In conclusion, because of its once-daily dosing, efficacy, and cost, omeprazole may soon be considered as fIrst-line Phase II therapy for GERD. A decision analysis was performed to assess clinical and economic effects of three treatments: Phase I therapy alone or in combination with either omeprazole (20 mg/day) or ranitidine (150 mg twice daily) therapy. Although the omeprazole therapy was the most expensive, it relieved GERD symptoms and reduced payments required from third party payers for treatment of complications and surgery.6 When the cost-effectiveness of omeprazole (40 mg/ day) and ranitidine (300 mg to 600 mg/day) therapy was compared, omeprazole's healing rates were faster. In addition, omeprazole-treated patients used fewer antaCids, and use of endoscopy was projected to decrease because of clinicians' greater confidence in omeprazole's healing ability. Thus, the authors concluded that omeprazole was more costeffective overall than ranitidine. 4

Sucralfate Although sucralfate (Carafate, Sulcrate-Hoechst Marion Roussel) is used clinically to treat GERD in some settings, this agent is not FDA approved for GERD treatment. Sucralfate is a sulfated disaccharide complex with aluminum hydroxide. It adheres to damaged mucosal tissue, creating a barrier to the irritant effects of acid, pepsin, and other components of gastric contents. Sucralfate does not alter the pH of the gastric contents or affect gastric acid secretion. 5 Virtually no sucralfate is absorbed, so adverse systemic effects are uncommon. Thus, sucralfate is well tolerated, with constipation being the most commonly reported adverse effect. The absotption of aluminum in sucralfate can be a potential problem in renally impaired patients.39 Chronic ingestion can also result in increased serum aluminum concentrations, and hypophosphatemia can occur following sucralfate binding of dietary phosphate. 2 Sucralfate in tablet form can be swallowed or dissolved in water to form a suspension. A suspension formulation is currently being manufactured for widespread use. Drug interactions with sucralfate usually result from chelation with the aluminum portion of the molecule (fable 7, page 22). Drug interactions may be avoided by administering other medications at least two hours before sucralfate administration. 4 Results of studies of sucralfate's efficacy in GERD have been inconsistent. In a study of 18 patients with esophagitis who received sucralfate 1 gram four times daily, 94% showed improvement after 12 weeks.2 However, a multicenter, randomized, double-blind, placebo-controlled trial was unable to demonstrate SignifIcant differences between the results of taking a sucralfate suspension (1 gram after meals and Journal of the American Phannaceutical Assodation

2 grams at bedtime) or a liquid placebo treatment. 40 The role of sucralfate in GERD management remains to determined. Although anecdotal reports suggest that s ! fate is effective in some patients, especially those with esophagitis, further studies must confirm its efficacy.

Prokinetic Agents Drugs that increase transit time of material throughout GI tract are called prokinetic agents. Currently, three p netic agents are available in the United States: bethanec (Urecholine-Merck), a cholinergic agonist; metoclop . (Reglan-Robins), a dopamine-receptor antagonist; and ti apride (propulsid-]anssen), a serotonin-4 (5-HT4) ago' Erythromycins also increase gastric motility but are not rently being used for GERD treatment.41 Bethanechol increases LES pressure, amplitude of GI con . tions, and esophageal clearance. However, it has no effect gastric emptying or coordination of GI contractions. For reason, bethanechol is not regarded as a true prokine)l agent. 8 ,41 In addition, increased gastric add secretion induCt by bethanechol could negatively affect a patient wu GERD.18,41,42 Bethanechol is poorly absorbed, requiring Up:1 90 minutes before its full GI effects are seen.4 In additioc patients do not tolerate bethanechol well. Adverse effects ed to its cholinergiC actions include abdominal pain an cramps, diarrhea, urinary frequency, blurred vision, snee · sweating, salivation, and increased blood pressure.4,lO,! Bethanechol is contraindicated in patients with asthma, c obstructive pulmonary disease, and peptic ulcer disease. 2 Metoclopramide increases LES pressure and gastric emp . Although data are conflicting, metoclopramide may a1~ increase esophageal peristalsis and clearartce.2 Absorptioni rapid and virtually complete; however, it may take up to 60 Din utes for GI effects to occur. 4 The elimination half-life of met pramide is 2.5 to 5 hours, and it is excreted in the urine. 41 Like bethanechol, metoclopramide produces adve effects, including drowsiness, jitteriness, tremors, nightrnalfl anxiety, and depression. Neurologic and dystonic reacti also have been reported. 4 ,8 Because metoclopramide can GI transit time, absorption of other drugs may be affe (fable 7, page 22). Use of drugs that decrease GI motility antagonize metoclopramide's effects. In addition, its use ' some antihypertensives and other medications that dep the CNS may lead to enhanced CNS depression. Cisapride, a newer oral prokinetic agent, appears to havebetter side-effect profile than metoclopramide. Its mech . of action is thought to be enhancement of acetylcholine rei at the myenteric plexus. Its in vitro action as a seroto ' (5-HT4) receptor agonist may be responsible for cisapride's . ity to increase GI motility. Rapidly absorbed after oral a .. tration, dsapride reaches peak plasma concentrations in 60. 90 minutes. It is approximately 35% to 40% bioavailable, about 98% is bound to plasma proteins. The recommen

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dosage of this medication is 10 mg four times daily.31 In two p]acebo-controlled studies, 10 mg and 20 mg four times daily showed beneficial effects on nighttime regurgitation. However in another placebo-controlled study, these effects were not seen. 43 Cisapride's advantage appears to be its favorable safety profile; the most commonly reported side effects are diarrhea, abdominal pain, constipation, flatulence, dyspepsia, rhinitis, upper respiratory infection, pain, fever, upper urinary tract infection, micturition frequency, and headache. 31 In conclusion, results from studies of the currently available prokinetic agents for GERD treatment have been conflicting. However, because these agents are poorly tolerated, they are not commonly used alone. They are primarily reserved for adjunctive therapy with H2-receptor antagonists. 8

Maintenance Therapy Once healing or symptomatic relief of GERD is achieved, patients frequently need maintenance therapy. As many as 80% to 90% of patients with healed esophagitis experience relapse after six months. 36,44 Because of an established safety profile during long-term therapy, the H 2-receptor antagonists are most commonly used as maintenance therapy in patients with GERD.8 To prevent recurrence, gastric acid suppression must occur throughout the day and night. However, typical maintenance dosages for duodenal ulcers, for example, ranitidine 150 mg once daily, often lead to relapse in many patients. In a randomized, double-blind trial of 61 patients with healed esophagitis, relapse rates of 42% and 36% occurred after six months of ranitidine 150 mg at bedtime and placebo, respectively.45 In a 12-month comparative trial, no significant differences in relapse rates were seen in patients treated with placebo, cimetidine 300 mg twice daily, or cimetidine 400 mg at bedtime. 2,26 Small studies have shown that H2-receptor antagonist therapy at standard peptic ulcer disease dosages may prevent relapse. 26 Omeprazole has also been studied as possible maintenance therapy for GERD. In a study of 73 patients with healed esophagitis, 14 experienced an endoscopically determined relapse after six months of omeprazole 20 mg once daily. Of the 14 patients whose condition relapsed, 12 experienced healing after the dosage was increased to 40 mg once daily; the remaining 2 patients experienced healing after the omeprazole dosage was increased to 60 mg daily.45 In a comParison of omeprazole (20 mg daily) with ranitidine (150 mg twice daily), 25% of the omeprazole-treated patients experienced relapse after one year, whereas the relapse rate was more than 80% for the ranitidine-treated patients. 2 Although omeprazole appears to be effective in preventing recurrences, there are concerns about omeprazole's long-term safety. Currently, peptic ulcer treatment doses of H2-receptor antagonists (divided into multiple daily doses) are the recommended therapy for GERD prophylaxis. 8 ,26,46 Omeprazole should be reserved for patients who do not respond to Vol NS36, No. 1

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Hz-receptor antagonist maintenance therapy. No studies have detennined the adequate duration of maintenance therapy.

Conclusions Pharmacists who are aware of both classic and atypical presentations of GERD can identify and refer patients appropriately, thereby avoiding potential complications of untreated disease such as hemorrhage, obstruction, aspiration, or malnutrition. In mild cases of GERD, antacid or alginic acid therapy and avoidance of certain foods and medications frequently produce resolution or control of symptoms. However, in patients with more severe disease, physician referral is required so that appropriate therapy, such as H2-receptor antagonists or omeprazole, may be prescribed. These drugs have proven efficacy in suppressing gastric acid secretion and in promoting healing of damaged tissue in patients with GERD. The H2-receptor antagonists must be given at least twice daily and, if necessary, in high doses (e.g., ranitidine 600 mg to 900 mg daily) for at least eight weeks. Omeprazole treatment should be initiated at 20 mg daily for four to eight weeks, although higher dosages may be necessary (e.g., 40 mg to 60 mg daily). If healing has not occurred after an eight-week trial, omeprazole can be continued for another four weeks. Maintenance therapy is often necessary for patients with GERD even after healing has occurred. H2receptor antagonists in split doses or omeprazole once daily have been used to prevent recurrence. The pharmacist can monitor and assess efficacy and tolerance of therapy by que~tioning patients frequently about their treatment. For example, pharmacists should solicit information about whether or not symptoms have decreased and whether patients have experienced adverse effects, such as constipation or diarrhea with antacids; diarrhea, headache, drowsiness, fatigue, muscle pain, or constipation with H2receptor antagonists; and headache, diarrhea, abdominal pain, nausea, vomiting, dizziness, or rash with omeprazole. Furthermore, pharmacists should monitor patient profiles for clinically significant drug interactions. For example, tetracycline and iron preparations cannot be fully absorbed when administered with antacids. Also, warfarin, phenytOin, and theophylline concentrations may be increased when administered with Hzreceptor antagonists, especially cimetidine. Finally, diazepam, phenytoin, and warfarin levels may increase because of omeprazole's inhibition of the cytochrome P-450 enzyme system. Such drug interactions become particularly important when the acid-reducing agent is either initiated or discontinued. In conclusion, the pharmacist is the ideal health care professional for recognizing typical and atypical signs of GERD; assessing severity of symptoms; recommending Phase I ther- I apy, including antacid/alginic acid therapy in mild disease; and Journal of the American Pbarmaceutical Association

providing physician referral if symptoms persist or if atypical signs are present. Kathy L. Koppelo, PharmD, is a pharmacist at Ruby Memorial Hospital, Morgantown, W.Va. At the time the article was written, Koppelo was a pharmacy practice resident at Charleston Area Medical Center, Charleston, W. Va. Barbara Kaplan, PharmD, is assistant professor of clinical pharmacy and clinical assistant professor offamily medicine, Schools of Pharmacy and Medicine, West Virginia University, Charleston.

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