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									Pharmacotherapy of Duodenal and Gastric Ulcerations

Marie A. Chisholm1,2
College of Pharmacy, The University of Georgia, Athens GA 30602


PROLOGUE
Peptic ulcer, an excavation in the mucosal lining penetrating
below the muscularis mucosa of the stomach or duodenum
(See Figure 1), is a common disorder. The incidence varies
with the age, gender, and geographical location with duode-
nal ulcers occurring in approximately four to ten percent of
the United States (U.S.) population and gastric ulcers occur-
ring in less than one percent. Both gastric and duodenal
ulcers are associated with severe complications including
hemorrhages, perforations, gastrointestinal obstruction, and
malignancy.
     Peptic ulcer disease and its complications cost the U.S.
health care budget greater than three billion dollars annu-
ally. Based on the high incidence and the enormous amount
of money that is spent on peptic ulcer disease, it is very
important for pharmacists and pharmacy students to be
educated about this disease and the medication regimens
used to treat it. This lecture provides a basic review of the
pathophysiology, clinical presentation and evaluation, and
medications used to treat uncomplicated duodenal and
gastric ulcerations.

ETIOLOGY, PATHOPHYSIOLOGY, AND
PATHOGENESIS
  Peptic ulcers usually occur as a result of an imbalance
between mucosal protective factors and aggressive factors.
Significant gastric protective factors include mucus secre-
tion, bicarbonate secretion, mucosal blood flow, cell growth
and prostaglandins. By continuously secreting onto the                     Fig. 1. Esophagus, stomach, duodenum, and stomach wall. Esopha-
gastric mucosa, mucus which is secreted by goblet cells                    gus, stomach, and duodenum. The stomach can be divided into four
protects underlying gastric cells and acts as a lubricant layer            major regions: cardia, fundus, body, and pyloris. The cardia is the
between the gastric mucosa and its contents. Bicarbonate,                  region immediately below the gastroesophageal sphincter, the fun-
which is secreted by the pancreas, biliary system and gastric              dus is the dome-shaped portion of the stomach, the body is the large
epithelial cells, protects by neutralizing luminal hydrogen                central portion of the stomach, and the pylorus is the funnel shaped
ions in the gastric lumen. Gastrointestinal (GI) blood flow is             terminal portion. The duodenum, the first portion of the small
essential in maintaining mucosal integrity and preventing                  intestine, is after the pyloric sphincter (which is the “gatekeeper” that
against vascular insufficiency, whereas, epithelial cell growth            regulates the movement of chyme into the small intestine and prohib-
                                                                           its backflow).
plays an important role in restoring damaged epithelium.                    The wall of the stomach. The muscularis layer of the wall is below
Endogenous prostaglandins, in particular PGE2 which is                      the muscosa region and consists of three layers - oblique muscle,
secreted by gastric and duodenal mucosal cells, aids in                     circular muscle, and longitudinal muscle. The serosa, or visceral
mucosal protection by stimulating mucus and bicarbonate                     peritoneum, is the outer layer of the stomach and it consists of an
secretion, maintaining blood flow, and participating in epi-                inner layer of connective tissue. Peptic ulcers penetrate the muscularis
thelial cell growth(1,2).                                                   mucosa.
     Peptic ulcers derive their name from pepsin, a digestive              pepsinogen, which is secreted from chief cells, to pepsin. In
enzyme found in gastric juices that hydrolyzes peptide bonds               addition to pepsin, there are many other important noxious
to break down protein. Pepsin is derived from a series of                  factors including Helicobacter pylori, nonsteroidal anti-in-
steps involving hydrochloric acid that converts the enzyme                 flammatory drugs (NSAIDs) and gastric acid that play an
1                                                                          aggressive role in the development of ulcers (See Figure 2).
    Assistant Professor of Pharmacy Practice.
                                                                           Evidence is now available that supports that H. pylori and
2
    Authors’ address: Medical College of Georgia, Clinical Pharmacy Pro-
    gram, CJ-1020, Augusta GA 30912-2390                                   NSAIDs account for the majority of peptic ulcers(3-5).


196                                       American Journal of Pharmaceutical Education Vol. 62, Summer 1998
                                                                           Table I. Drugs that may                   commonly       cause
                                                                           gastrointestinal mucosal injury
                                                                           Aspirin
                                                                           Chemotherapeutic agents
                                                                           Corticosteroids
                                                                           Ethacrynic acid
                                                                           Ethanol
                                                                           Nonsteroidal anti-inflammatory agents
                                                                           Pancrease supplementation
                                                                           Potassium chloride
                                                                           Reserpine
                                                                           Warfarin


                                                                           tic ulcer disease who are not taking NSAIDs have H. pylori, it
                                                                           is important to note that H. pylori is a very common infection
                                                                           and most infected individuals do not have peptic ulcers.
                                                                           Therefore, it is not known whether the presence of H. pylori
                                                                           within the GI tract is pathologic in and of itself. This lends to
                                                                           the suspicion of the involvement of other factors such as the
                                                                           immune system and H. pylori strain variability playing impor-
                                                                           tant roles in the protection or development of peptic ulcers.
                                                                           The importance of the immune system in the formation of
Fig. 2. Parietal cell and acid secretion. The release of histamine from    peptic ulcers and mechanisms identifying population subsets
the mast cells activates the proton pump of the parietal cell by           at risk for ulcer development deserves further investigation.
increasing intracellular cyclic adenosine monophosphate (cAMP).            In order to reduce the number of infected individuals,
Gastrin and acetylcholine contribute to acid release by increasing         understanding transmission methods of H. pylori is neces-
intracellular calcium. Through a series of intracellular events, the net   sary. Transmission of H. pylori is believed to occur primarily
result is a 1:1 exchange of an intracellular hydrogen ion for a luminal    by the fecal-oral and oral-oral routes. Prevalence of infec-
potassium ion.                                                             tion is also related to age and socioeconomic classes with
                                                                           higher incidences reported in the elderly and the lower
Peptic Ulcerations and H. pylori                                           socioeconomic groups(13). Cases of H. pylori transmission
     H. pylori is a spiral-shaped, flagellated, Gram-negative              by infected instruments, such as endoscopes, have also been
organism that, if present, is found between the gastric mucus              reported(4,11).
layer and surface epithelial cells in the gastric epithelium. H.
pylori penetrates the mucus layer by producing large amounts               Peptic Ulcerations and NSAIDs
of urease, which breaks down urea and converts it to ammo-                      The second most common form of peptic ulcers is
nia and carbon dioxide thereby allowing the organism to                    NSAID-associated ulcers(2,6,14,15). Two to four percent of
withstand the harsh environment of the GI tract(4,5).                      patients who take NSAIDs will have GI damage(3). Chronic
     Walsh and colleagues revealed three lines of evidence                 NSAID-therapy produces gastric injury by two mecha-
supporting the hypothesis that gastritis due to H. pylori is a             nisms. The first is by a direct caustic action on the mucosa
major factor causing peptic ulcerations(6). First, greater                 and the second is by a systemic effect whereby endogenous
than 95 percent of patients with duodenal ulcers and more                  prostaglandin synthesis is inhibited. Individuals that con-
than 80 percent of patients with gastric ulcers are infected               sume large amounts of NSAIDs, such as patients suffering
with H. pylori, excluding individuals with gastrinoma (a                   from arthritis and the elderly, are extremely susceptible to
gastrin-secreting tumor associated with Zollinger-Ellison                  the development of ulcers.
syndrome) and those taking NSAIDs(6-8). Second, duode-
nal ulcers develop far more frequently in people infected                  Risk Factors for Ulcer Development
with H. pylori than in non-infected persons(9). Third, recur-                   A number of risk factors can predispose an individual to
rence of both duodenal and gastric ulcers is markedly de-                  develop peptic ulcers or delay ulcer healing. Of course, the
creased after eradication of H. pylori(10,11). Collectively,               most important risk factors for developing peptic ulcers are
information supporting H. pylori and its association with the              the use of NSAIDs and H. pylori infection. Many reports
development of GI ulcerations are overwhelmingly con-                      have demonstrated that cigarette smoking impairs ulcer
vincing. Data also suggest an association between H. pylori                healing and promotes ulcer recurrence. The role of genetic
and gastric cancer with approximately 80 to 90 percent of                  factors, psychological stress, and dietary foods in ulcer
individuals with gastric cancer testing seropositive for H.                formation is controversial and remains uncertain(3).
pylori-antibodies(3).                                                           Many diseases have been associated with peptic ulcer
     The exact pathophysiologic mechanisms by which H.                     development. Chronic pulmonary disease and rheumatoid
pylori causes ulcers remains unknown. One theory suggests                  arthritis, two common diseases, have been linked to gastric
that H. pylori damages mucosal defense by producing toxins                 and duodenal ulcers. Using steroids and smoking cigarettes
and evoking inflammation. Ammonia, protease, lipase, and                   may contribute to the increased rate of peptic ulcers in
cytotoxins have all been indicated as caustic elements. Some               patients suffering from chronic pulmonary disease, and the
studies suggest that H. pylori-infection indirectly produces a             use of NSAIDs to reduce pain and inflammation may con-
defect in controlling acid secretion by increasing gastrin-                tribute to the increased rate of peptic ulcerations in rheuma-
releasing peptides(12). Although nearly all patients with pep-             toid arthritis patients.
                                        American Journal of Pharmaceutical Education Vol. 62, Summer 1998                               197
                                                                      Fig. 4. Upper GI Radiograph. Upper GI series revealing the stomach
                                                                      (large arrow) and duodenum (small arrow).

                                                                     should ask the patient questions to ascertain the account of
                                                                     the gastrointestinal problem including the setting in which it
                                                                     developed, intensifies, and alleviates. A complete drug his-
                                                                     tory to identify medications that may contribute to the
                                                                     development of gastritis or ulcerations is also imperative(17).
                                                                     See Table I.
Fig. 3. Esophagogastroduodenoscopy revealing a peptic ulcer.              More than 95 percent of duodenal ulcers occur in the
Esophagogastroduodenoscopy revealing a 4-mm ulcer (arrows)           first portion of the duodenum and approximately 90 percent
penetrating the wall of the duodenum.                                of these are located within 3 cm of the junction of the pyloric
                                                                     and duodenal mucosa. Duodenal ulcers are usually round or
CLINICAL PRESENTATION                                                oval, but may be irregular or elliptic and are usually less than
Patients with duodenal and gastric ulcers often present with         1 cm in diameter (see Figure 3). Most all benign gastric
dyspeptic symptoms such as abdominal pain, nausea, and               ulcers are found immediately distal to the junction of the
vomiting. Epigastric pain typically described as burning, gnaw-      antral mucosa. Diagnosis of peptic ulcers depends on visu-
ing, and aching is the most common complaint. Non-specific           alizing ulcers by radiologic or endoscopic methods. Barium
dyspeptic complaints such as belching, bloating, abdominal           contrast radiology can detect 30 to 80 percent of peptic
distention, and food intolerance occur in approximately 40 to        ulcers, whereas, endoscopy can detect more than 90 percent
70 percent of peptic ulcer disease patients. The intensity of the    of peptic ulcers. Although a 24-hour pH study may be
pain and other symptoms vary from patient to patient. Food           valuable in some patients in whom acid secretion is ques-
may alleviate the pain of duodenal ulcers or, conversely,            tionable, pH tests are not commonly used and are thought to
intensify the pain of gastric ulcers. Therefore, epigastric pain     provide little additional information in evaluating uncom-
that occurs when the stomach is empty (e.g., pain during the         plicated GI ulcerations where acid hypersecretion is not
night or between meals) and is relieved by food is typical of        suspected. Tests to measure pH are frequently used to
duodenal ulcers and pain that occurs within two hours of             evaluate patients with suspected gastroesophageal reflux
eating is typical of gastric ulcers. Because of this, weight loss    disease (the passage of gastric contents from the stomach
is common in individuals suffering with gastric ulcerations and      into the esophagus) or Zollinger-Ellison syndrome (a se-
weight gain may occur in individuals suffering with duodenal         vere form of peptic ulcer disease in which intractable ulcers
ulcerations. It is equally important to recognize that pain does     are accompanied by extreme gastric hyperacidity and at
not necessarily correlate with the presence of an ulcer. In fact,    least one gastroma).
many patients may be asymptomatic. The elderly, individuals               Radiologic procedures are used in visualizing craters of
taking analgesics, and people who have a high pain tolerance         peptic ulcers. An “upper gastrointestinal series,” a common
often experience a “silent ulcer,” meaning that they are symp-       procedure used to evaluate the presence of peptic ulcers,
tom free until an ulcer related complication appears such as         refers to the radiographic visualization of the esophagus,
gastrointestinal bleeding (often suggested by hematoemesis           stomach, and small intestine. To enhance the visualization
or melena), perforation and obstruction.                             of structures, barium sulfate, a contrast agent, is usually
                                                                     administered orally to patients at the beginning of upper
CLINICAL EVALUATION                                                  gastrointestinal radiographic procedures (see Figure 4).
A comprehensive patient history is critical when evaluating               An endoscope is an illuminated optical, tube-like in-
patients with peptic ulcer disease complaints. The clinician         strument designed to inspect the interior of the GI tract.
198                                 American Journal of Pharmaceutical Education Vol. 62, Summer 1998
Esophagogastroduodenoscopy (EGD) is partially inserted              be given at least one to two hours apart from other medica-
(via the oral cavity) into the patient and is used to directly      tions. Due to frequent administration and adverse effects,
visualize and examine the esophagus, stomach, and duode-            antacids are primarily used for relieving ulcer pain and are
num (see Figure 3). Endoscopy not only allows visualization         often used in combination with other antiulcer agents.
of ulcers, but provides opportunities to collect gastric biop-
sies to detect for H. pylori or malignancy. Since up to 10          Histamine2-Receptor Antagonists
percent of gastric ulcers are malignant, follow-up endoscopy             Currently, there are four H2-receptor antagonists
is extremely important in these patients.                           (cimetidine, famotidine, nizatidine, and ranitidine) that are
     Laboratory tests are used to evaluate patients with GI         commercially available in the U.S. These agents bind to H2-
symptoms. Although complete blood counts may not be                 receptors on the parietal cell, thereby diminishing cyclic
useful in diagnosing peptic ulcer disease, it is extremely          AMP production and the secretion of gastric acid (see
valuable in diagnosing and evaluating anemia, a common              Figure 2). Cimetidine, famotidine, nizatidine, and ranitidine
complication of GI ulcerations. Serology is also used to            are fairly effective and have similar duodenal ulcer healing
detect the presence of H. pylori-antibodies, which becomes          rates, 82 to 95 percent healing within eight weeks of
extremely useful when designing a pharmacotherapeutic               therapy(18,19). Numerous drug interactions have been re-
treatment plan. Although serology only indicates whether            ported with cimetidine due to its effects on inhibiting the
the patient has been exposed to H. pylori, it may, however,         hepatic cytochrome P-450 system CYP IIIA4, IID6, IIE1,
indicate active infection in patients who have not had prior        1A2, and IIC9 isoenzymes, thereby decreasing hepatic clear-
H. pylori eradication therapy.                                      ance of many drugs such as warfarin, theophylline, and
     Biopsies of the stomach taken for histology, culture,          propranolol. Cimetidine has also been associated with con-
gram stain or detection of antibodies are used to determine         fusion, gynecomastia, and impotence. Generally, H2-recep-
the presence of H. pylori. For example, the “CLO”                   tor antagonists are safe and well tolerated. Side effects
(Campylobacter-like organism) test has a colored pH indi-           associated with H 2 -receptor antagonists include
cator that undergoes a change in the presence of the gastric        thrombocytopenia, drowsiness, nausea, vomiting, skin rash,
biopsy when ammonia is generated by H. pylori. By exploit-          and headache. All H2-receptor antagonists should be ad-
ing the unique capability of H. pylori to produce urease,           justed in patients with renal dysfunction. See Table II for
13
   Carbon and 14Carbon breath tests detect the presence of          dosages of specific agents.
H. pylori by measuring urease activity. Breath tests involve
the administration of radioactive carbon-urea which will            Proton Pump Inhibitors
yield labeled carbon dioxide in the presence of urease. This             Currently, there are two proton pump inhibitors,
carbon dioxide enters the bloodstream and can be measured           omeprazole and lansoprazole, available in the U.S. Proton
in the expired air by having the patient blow-up a bal-             pump inhibitors suppress gastric acid secretion by inhibiting
loon(17).                                                           the parietal cell H+/K+- ATPase pump (see Figure 2) and are
                                                                    more effective in healing ulcers than H2-receptor antago-
TREATMENT                                                           nist(20,21). Although omeprazole is relatively well toler-
Treatment of peptic ulcers is aimed at relieving pain, expe-        ated, it is a hepatic cytochrome P-450 IIC enzyme inhibitor
diting ulcer healing, reducing ulcer associated complica-           and a cytochrome P-450 1A2 enzyme inducer. When used
tions, eradicating H. pylori infection if present, and minimiz-     together, omeprazole has been reported to increase concen-
ing ulcer recurrence. The following describes the most com-         trations of phenytoin and warfarin. Because of profound
monly used agents to treat duodenal and gastric ulcers.             and long lasting inhibition of gastric acid secretion, proton
                                                                    pump inhibitors may interfere with absorption of drugs
Antacids                                                            where pH is a determinant of bioavailability such as with
    Frequent and high doses of antacids (100-144 mEq of             ketoconazole, itraconazole, ampicillin esters, and iron salts.
acid neutralizing capacity one and three hours after meals          Omeprazole and lansoprazole are most effective when taken
and at bedtime) are effective in healing peptic ulcers. In          in the morning before meals, and omeprazole capsules
addition to their acid-neutralizing effects, antacids heal          should be swallowed whole, not chewed, crushed, or opened.
ulcers by enhancing mucosal defense. Antacids are avail-            For patients who have difficulty swallowing capsules,
able as magnesium hydroxide, aluminum hydroxide, cal-               lansoprazole can be opened and the intact granules within
cium, or sodium salts. Because single salt antacids are often       can be sprinkled on a medium such as one tablespoon of
associated with GI adverse effects such as diarrhea with            applesauce and swallowed immediately (do not chew or
magnesium hydroxide antacids and constipation with cal-             crush the granules). See Table II for recommended dosages.
cium carbonate antacids or aluminum hydroxide antacids,
the most widely used antacids are mixtures (i.e., aluminum          Sucralfate
hydroxide and magnesium hydroxide antacids). In addition                 In the presence of acid, sucralfate forms an adhesive that
to decreasing GI adverse effects, antacid mixtures generally        binds electrostatically to ulcer craters forming a protective
provide more sustained action than single agents. Antacids          barrier that covers the ulcer site and protects it against further
are associated with many drug interactions and adverse              attack by acid, pepsin, and bile salts. Studies have demon-
events. For example, calcium carbonate antacids are usually         strated that sucralfate is comparable to the effectiveness of
avoided because they are associated with acid rebound,              H2-receptor antagonists in healing ulcers. To prevent adverse
therefore delaying pain relief and healing. Antacids may            effects associated with aluminum toxicity, sucralfate should
impair absorption of many drugs including H2-receptor               be used in caution with chronic renal failure patients who
antagonists and they also reduce mucosal binding of                 have impaired excretion of absorbed aluminum. Because of
sucralfate, thus decreasing their therapeutic effects.              the potential for sucralfate to alter the absorption of some
In order to prevent absorption interactions, antacids should        drugs, separate administration (two hours before or after) of

                                    American Journal of Pharmaceutical Education Vol. 62, Summer 1998                             199
Table II. Dosing and laboratory monitoring of histamine2-receptor antagonists, sucralfate, and proton pump
inhibitors
                                                                                                 Medication
                                                                                                 laboratory
                                                  Intravenous     Dose adjustment in             monitoring
                 Indications      Oral dose       dose            renal dysfunction              parameters *
 H2-Receptor inhibitors
   Cimetidine    Duodenal ulcer
   (Tagamet®)       Active        800 mg HS       300 mg Q 6-8 hr CrCl <30 mL/min - 300mg q 12 h SCr, AST,ALT
                                  400 mg BID or                                                     BUN, RBC,
                                  300 mg QID                                                        Platelets, WBC
                    Maintenance   400 mg HS
                 Gastric ulcer
                    Active        300 mg QID or 300 mg Q6-8 hr
                                  800 mg HS
                    Maintenance   400 mg HS
 Famotidine      Duodenal ulcer
   (Pepcid®)        Active        20 mg BID or    20 mg Q 12 hr   CrCl <10 mL/min - 20mghs       SCr, AST,ALT
                                  40 mg HS                                                          BUN, RBC,
                    Maintenance   20 gm HS                                                          Platelets, WBC
                 Gastric ulcer
                    Active        40 mg HS
 Nizatidine      Duodenal ulcer
   (Axid®)          Active        150 mg BID or                   CrCl 20-50mL/min - 150 mg qd   SCr, AST,ALT
                                  300 mg HS                       CrCl <20 mL/min - 150 mg qod      BUN, RBC,
                    Maintenance   150 HS                                                            Platelets, WBC
                 Gastric ulcer
                    Active        150 mg BID or
                                  300 mg HS
 Ranitidine      Duodenal ulcer
   (Zantac®)        Active        150 mg BID or 50 mg Q 6-8 hr CrCl <50mL/min - 150 mg qd        SCr, AST,ALT
                                  300 mg HS                                                         BUN, RBC,
                    Maintenance   150 mg HS                                                         Platelets, WBC
                 Gastric ulcer
                    Active        150 mg BID      50 mg Q 6-8 hr
Mucosal Defense Enhancer
Sucralfate      Duodenal ulcer                                                 No adjustment recommended             Aluminum, BUN,
  (Carafate®)     Active                 1 gm QID or                                                                    SCr
                                         2 gm BID
                      Maintenance        1 gm BID
Proton Pump Inhibitors
Omeprazole
  (Prilosec®)  Duodenal ulcer            20-40 mg QD                           No adjustment recommended             SCr, BUN, WBC,
               Gastric ulcer             20-40 mg QD                                                                   ALT, AST,
                                                                                                                       CBC
Lansoprazole
  (Prevacid®)      Duodenal ulcer        15 mg QD                              No adjustment recommended             SCr, BUN, WBC,
                   Gastric ulcer         15 mg QD                                                                      ALT, AST,
                                                                                                                       CBC
*ALT=alanine transamine, AST=aspartate transaminase, BUN=blood urea nitrogen, CBC=complete blood count, RBC=red blood cell count, SCr=serum
 creatinine, WBC=white blood cell count

medications should be considered when alterations of                    of NSAID-induced gastric ulcers and should be considered
bioavailability are believed to be critical. For treating active        for those patients who absolutely need to use NSAIDs and
peptic ulceration, sucralfate should be taken on an empty               are at a high risk for developing peptic ulcers. At doses above
stomach at least one hour before meals and at bedtime. See              200 meg daily, misoprostol has both antisecretory and mu-
Table II for recommended dosages. Sucralfate is generally               cosal protective factors. Protective properties of misoprostol
safe with the most common adverse effect being constipation.            are due to its ability to increase bicarbonate and mucus
                                                                        production. The recommended dose of misoprostol approved
Misoprostol                                                             for the prevention of NSAID-induced gastric ulcers is 200
    Discontinuing medications that can induce gastritis or              meg four times daily. Misoprostol does not interfere with the
ulcerations is extremely important in the therapeutic treat-            beneficial effects of NSAIDs. The most frequent side effects
ment and prevention of peptic ulcers. Misoprostol, a syn-               associated with misoprostol are abdominal pain and diar-
thetic PGE1 analogue, is FDA approved for the prevention                rhea. Approximately 25 to 40 percent of patients receiving



200                                   American Journal of Pharmaceutical Education Vol. 62, Summer 1998
Table III. Common regimens used for H. pylori eradication and cure rates
Regimen                                                                                                    Cure rates (95% CI*)
Amoxicillin 1 gm QD + Omeprazole 20 mg BID + Clarithromycin 500 mg BID for 7 days                          86-91
Bismuth subsalicylate 2 tablets QID + Metronidazole 250 mg QID + Amoxicillin 500 mg QID for 7 days         75-81
Bismuth subsalicylate 2 tablets QID + Metronidazole 250 mg QID + Amoxicillin 500 mg QID for 14 days        80-86
Bismuth subsalicylate 2 tablets QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID for 7 days        86-90
Bismuth subsalicylate 2 tablets QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID for 14 days       88-90
Bismuth subsalicylate 2 tablets QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID + Omeprazole 20   94-98
mg BID for 7 days
Clarithromyicin 500 mg BID + Amoxicillin 1 gm BID + Lansoprazole 30 mg BID for 14 days                     86-91
Clarithromycin 500 mg TID for 14 days + Omeprazole 20 mg BID for 14 days + then Omeprazole 20 mg qd for    83-90
14 days
Metronidazole 500 mg BID + Omeprazole 20 mg BID + Clarithromycin 500 mg BID for 7 days                     87-91
Metronidazole 250 mg QID + Omeprazole 20 mg BID + Amoxicillin 1 gm QD for 7-14 days                        77-83
Ranitidine Bismuth Citrate (Tritec®) 400 mg BID for 28 days + Clarithromycin 500 mg TID for 14 days        82-94
*CI= Confidence Interval

misoprostol develop diarrhea within two weeks of therapy           for eradication or duration of therapy is not known. Thus far,
and reduction of the dose may help to decrease the                 no single agent given as monotherapy for eradication has been
frequency and severity of the diarrhea. Other adverse              proven efficacious. Because of poor results with monotherapy
effects associated with misoprostol include nausea,                and the emergence of resistance to antimicrobials,
vomiting, and headache. Misoprostol can cause uterine              combination antimicrobial regimens are more effective than
contractions and subsequently belongs to Pregnancy                 single agents. Due to synergistic antimicrobial effects,
Category X; therefore, it is contraindicated in pregnant           therapies including proton pump inhibitors tend to have higher
women. Because of misoprostol abortifacient properties,            efficacy rates than those with H2-receptor antagonists.
it should not be initiated in women of childbearing                     Reasons for treatment failures with antimicrobial
potential until the possibility of pregnancy has been              therapy include the development of antibiotic resistance by
excluded and an effective method of contraception has              the organism, adverse drug reactions and poor compliance to
been started within two weeks of starting the drug.                medication therapy. The use of multiple agents often results
Eradication of Helicobacter pylori                                 in the patient experiencing a greater number of side effects
     Although H2-receptor antagonists, proton pump in-             which may adversely affect compliance(25). Fortunately,
hibitors, antacids, and sucralfate have impressive healing         most side effects are mild with only five percent of patients
rates, ulcer recurrence is common. Clinical trials have            actually having to discontinue therapy(26). Severe side
demonstrated that eradication of H. pylori not only results        effects from H. pylori eradication therapies such as
in healing of ulcers, but greatly reduces the risk of              pseudomembranous colitis are infrequent; however, minor
recurrence(22). Studies have suggested that the one-year           adverse effects may occur in up to 40 percent of patients.
recurrence rates of duodenal ulcer decreases from 70 to            Reactions include diarrhea and candidiasis with amoxicillin;
90 percent with antisecretory agents to less than 15               nausea, diarrhea and photosensitivity with tetracycline;
percent after eradication of H, pylori infection(23,24).           nausea, diarrhea, metallic taste and a disulfiram-like reaction
Furthermore, therapy for the eradication of H. pylori              with metronidazole; metallic taste, diarrhea, nausea and
appears to be more cost effective than acid suppression            headache with clarithromyin; and black stools and
therapy for treating duodenal and gastric ulcers(24).              discoloration of the tongue with bismuth. In addition to
     Currently, the American College of Gastroenterology           adverse effects, many H. pylori eradication regimens require
recommends that all patients diagnosed with H. pylori              patients to take numerous tablets daily, thus making therapy
associated peptic ulcers receive antimicrobial therapy             cumbersome and often resulting in a decrease in patient
effective against this organism(22). The FDA has approved          compliance. This demonstrates the important role that
several regimens for the treatment of peptic ulcer disease.        pharmacists can play in treating patients with peptic ulcers.
These include clarithromycin for two weeks plus concurrent         Pharmacists should encourage patients to comply with
omeprazole therapy for four weeks, clarithromycin for two          therapy and should educate patients as to what adverse
weeks plus concurrent ranitidine bismuth citrate (Tritec®)         effects are to be expected. Practitioners should take an
therapy for four weeks, and concurrent bismuth,                    individualized approach in treating patients with duodenal
metronidazole, tetracycline for two weeks plus an                  and gastric ulcers (see Appendix A and Figure 5). When
antisecretory agent for four weeks. Eradication rates for          designing eradication therapy, it is extremely important to
these regimens are 70 to 80, 80 to 85 and 73 to 84 percent,        consider the efficacy and safety profiles of the medications,
respectively(22). Helidac®, a new product approved for H.          patient compliance, patients prior exposure to antibiotics,
pylori associated duodenal disease, is used in combination         and cost- effectiveness.
with an antisecretory agent. Helidac® is a 14-day blister kit
containing bismuth subsalicylate and generic metronidazole         PATIENT EDUCATION
and tetracycline. Each blister card contains a one day supply      To promote efficacy and prevent adverse effects, patient
of medication (eight tablets of bismuth 262.4 mg, four             counseling is necessary. The patient should be advised to
tablets of metronidazole 250 mg, and four capsules of              take the medication as prescribed and for the entire duration
tetracycline 500 mg).                                              of therapy. If the patient smokes cigarettes, it is important to
     Examples of selected regimens which have undergone            counsel the patient on the adverse effects that smoking has
investigation can be found in Table III. The optimal therapy       on ulcer healing and advice patients that smoking should be

                                    American Journal of Pharmaceutical Education Vol. 62, Summer 1998                          201
                                                                      common. Although agents such as H2-receptor antagonists,
                                                                      proton pump inhibitors, antacids, and sucralfate have been
                                                                      used successfully to manage peptic ulcers, the recognition of
                                                                      H. pylori as a major culprit in the pathogenesis of peptic
                                                                      ulcers has significantly revolutionized the treatment of peptic
                                                                      ulcers. Eradication of this organism not only aids in ulcer
                                                                      healing but reduces ulcer recurrence. By eradicating H.
                                                                      pylori, many peptic ulcers can now be cured.
                                                                       Am. J. Pharm. Educ., 62, 196-203(1998); received 12/28/97, accepted 4/1/98.

                                                                       References
                                                                        (1) Konturek, S.J. and Konturek J.W., "Gastric adaption: Basic and
                                                                            clinical aspects," Digestion, 55,131-138(1994).
                                                                        (2) Wallace, J.L., "Prostaglandins. NSAIDs, and cytoprotection,"
                                                                            Gastroenterol. Clin. North Am., 21,631-641(1992).
                                                                        (3) Branch, M.S., Brazer, S.R. and Taylor, I.L., "Peptic ulcer disease:
                                                                            Medical and surgical management," in Principles and Practice of
                                                                            Gastroenterology and Hepatology (edit. Gitnik) Appleton & Lange,
                                                                            Norwalk CT (1994) pp.141-158.
                                                                        (4) Fennerty, M.B., "Helicobacter pylori," Arch. Intern. Med., 154,721-
                                                                            727(1994).
                                                                        (5) Tytgat, G.J. and Rauws, E.J., "Cdmpylobacter pylori and its role in
                                                                            pepticulcer disease," Gastroenterol. Clin. North Am.,19,183-196(1990).
                                                                        (6) Walsh J.H. and Peterson, W.L. "The treatment of Helicobacter pylori
                                                                            infection in the managementofpepticulcer disease," N. Engl.J. Med.,
                                                                            333, 984-991(1995).
                                                                        (7) Soil, A.H., "Gastric, duodenal, and stress ulcer," in Gastrointestinal
                                                                            Disease (edits. Sleisenger, M. and Fordtran, J.) WB Saunders, Phila
                                                                            delphia Pa (1993) pp. 580-679.
                                                                        (8) Graham, D.Y., "Helicobacter pylori: Its epidemiology and its role in
                                                                            duodenal ulcer disease," J. Gastroenterol. Hepatol.,6,105-113(1991).
                                                                        (9) Sipponen, P., Seppala, K., Aarynen, M., Helske, T. and Kettunen, P.,
Fig. 5. Uncomplicated acute peptic ulcer treatment algorithm.               "Chronic gastritis and gastroduodenal ulcer: A case control study on
                                                                            coexisting duodenal or gastric ulcer in patients with gastritis," Gut, 30,
avoided. Because of its toxic effects on the GI mucusa,                     922-929(1989).
patients should also be advised not to use NS AIDs including           (10) Rauws, E. J. and Tytgat, G.J., "Cure of duodenal ulcer association
over-the-counter NSAID products. Before dispensing any                      with eradication of Helicobater pylori," Lancet,335, 1233-1235(1990).
medications, pharmacists should question the patient con-              (11) Lee, A., "The microbiology and epidemiology of Helicobacter pylori
                                                                            infection," Scand. J. Gastroenterol., 29(Suppl 201), 2-6(1994).
cerning whether or not an adverse experience had occurred              (12) el-Omar, E.M., Pemen, I.D., Ardill, J.E., Chittajallu, R.S., Howii, C.
in the past while using this medication (if the patient used the            and McColl, K.E., "Helicobacter pylori infection and abnormalities of
medication before), and the physician should be notified in                 acid secretion in patients with duodenal ulcer disease," Gastroenterol.,
cases where individuals have experienced severe adverse                     109, 681-691(1995).
effects from the prescribed medication. Patients should be             (13) Lamber, J.R., Lin, S.K., Sievert, W., Nicholson, L., Schembri, M. and
                                                                            Guest, C., "High prevalence of Helicobacter pylori antibodies in an
informed to report if they experience worsening of GI symp-                 institutionalized population: evidence for person to person transmis
toms and other adverse events including dizziness, confu-                   sion," Am. J. Gastroenterol., 90,2167-2171(1995).
sion, depression, swelling in breasts, muscle stiffness, fever,        (14) Soll, A.H., Weinstein, W.M., Kurata, J.H. and McCarthy, D., "Non-
tinnitus, rashes, severe and persistent abdominal cramps,                   steroidal anti-inflammatory drugs and peptic ulcer disease," ibid., 114,
                                                                            307-319(1991).
diarrhea, nausea, vomiting, and headache. Because of its               (15) Graham, D.Y., "The relationship between nonsteroidal anti-inflam
abortifacient properties, it is extremely important that fe-                matory drug use and peptic ulcer disease," Gastroenterol. Clin. North
male patients of childbearing age who are receiving                         Am.,19,171-182(1990).
misoprostol comply with effective contraceptive measures               (16) Chisholm, M.A. and Jackson, M.W., "Evaluation of the gastrointes
while using this agent. One method often used to confirm                    tinal tract," in Pharmacotherapy: A Pathophysiologic Approach (ed
                                                                            its. DiPiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G.,
whether patients understand how to take their medications                   Posey, L.M.,) Appleton & Lange, Stamford CT (1997) pp. 663-673.
is to ask them to recite how they interpret to take the                (17) Brown, K.E. and Peura, D.A., "Diagnosis of Helicobacter pylori
medications including what activities and products to avoid.                infection," Gastroenterol. Clin. North Amer., 22,105-115(1993).
                                                                       (18) Feldman, M. and Burton, M.E. "Histamine2-receptor antagonists:
                                                                            Standard therapy for acid-pepcid diseases. Part I," N. Engl. J. Med.,
SURGERY                                                                     323,1672-1680(1990).
Failure to respond satisfactorily to medical treatment for             (19) Feldman, M. and Burton, M.E. "Histamine2-receptor antagonists:
peptic ulcers requires the consideration of surgery. Al-                    Standard therapy for acid-pepcid diseases. Part II," ibid., 323,1749-
                                                                            1755(1990).
though the true incidence of peptic ulcers not healed with             (20) Maton, P.N., "Omeprazole," ibid.,324,965-975(1991).
vigorous medication therapy is not known, with H. pylori               (21) Spencer, CM. and Faulds, D., "Lansoprazole: A reappraisal of its
eradication therapy, the vast majority of patients suffering                pharmacodynamic and pharmacokinetic properties, and its therapeu
with peptic ulcers can be treated successfully without under-               tic efficacy in acid-related disorders," Drugs, 48,404-430(1994).
going surgery(3).                                                      (22) Soil, A.H., "Medical treatment of peptic ulcer disease," JAMA, 275,
                                                                            622-629(1996).'
                                                                       (23) Ateshkadi, A., Lam, N. P. and Johnson, C. A., "Helicobacterpylpriepi
CONCLUSION                                                                  peptic ulcer disease," Clin. Pharm., 12,32-48(1993).
The occurrence of duodenal and gastric ulcerations are                 (24) Taylor, J.L., Zagari, M., Murphy, K. and Freston, J.M.,
                                                                            "Pharmacoeconomic comparison of treatments for the eradication of

202                                    American Journal of Pharmaceutical Education Vol. 62, Summer 1998
     Helicobacterpylori" Arch. Intern. Med., 157, 87-97(1997).                   •   Melenic stools and blood detected in rectal vault.
(25) Malfertheiner, P., "Compliance, adverse events and antibiotic resis
     tance in Helicobacter pylori treatment," Scan. J. Gastroenterol.,           •   EGD revealing a 4-mm ulcer in the duodenum.
     28(Suppl 196), 34-37(1993).
(26) Penston, J.G., "Helicobacter pylori eradication- understanding cau     2.   Could any of JB's problems be caused by drug therapy?
     tion but no execuse for inertia," Aliment. Pharmacol. Ther., 8, 369-        • JB has a history of aspirin use for back pain. Aspirin may
     389(1994).                                                                      cause mucosal erosions and ulcerations of the gastrointes
                                                                                     tinal tract, especially the stomach and duodenum.
                                                                                 • JB has also been using an antacid (Titralac Plus®) with a
APPENDIX A. PATIENT CASE STUDY                                                       high calcium content, which may contribute to his consti
                                                                                     pation.
CC:           "My stomach is killing me."
HPI:          JB is a 63 y o man who presents to the clinic with a three    3.   By reviewing JB's past and current medical history, list the two
              week history of epigastric pain, a two day history of              most likely causes of his ulcer.
              melenic stools, and constipation. Several weeks ago, he            • Aspirin use
              noticed the gradual onset of a localized epigastric pain           • Infection with H. pylori
              that has occurred daily, wavered in intensity, and
              increased at night. JB states that eating food or ingesting   4.   What are the goals for treating JB's peptic ulcer disease?
              Titralac Plus® seems to decrease the pain. He denies any           • Relieve pain and discomfort associated with peptic ulcer.
              past history of peptic ulcer disease and GI bleeding.              • Promote ulcer healing.
PMH:          Not significant                                                    • Prevent or treat complications of peptic ulcerations.
FH:           Both parents are deceased. He has two siblings that                • Eradicate H. pylori.
              are alive and well.                                                • Prevent ulcer recurrences.
SH:           He works as a carpenter, smokes approximately 1                    • Educate JB about peptic ulcer disease to improve compli
              pack of cigarettes per day, and is married with one                   ance and successful therapy.
              child.                                                             • Avoid adverse effects of medications.
Meds:         Titralac Plus® prn abdominal pain (several times
              daily)                                                        5.   Considering JB's presentation, what non-pharmacologic al
              Aspirin prn for back pain                                          ternatives are available to treat his peptic ulcer?
Allergies:     NKA                                                               • Since smoking is strongly correlated with delayed ulcer
ROS:          Unremarkable except for complaints noted above                          healing and recurrent disease, JB should be advised to
PE:                                                                                   stop smoking.
GEN:      Well-nourished, middle aged male                                       • Ingestion of foods and liquids that contribute to epigas
VS:       BP136/80; P72; RR14 reg; Temp 37.20 C; Ht 180 cm,                           tric pain should be limited or avoided.
          Wt 95 kg (84 kg 4 months ago)                                          • Since mucosal damage has been reported with the use of
HEENT: PERRLA; EOMI; discs flat; no AV nicking,                                       aspirin, JB should be advised to stop taking aspirin therapy.
          hemor-rhages, or exudates                                                   If a medication for pain relief is need, acetaminophen
COR:      S1 and S2 normal; no murmurs, rubs, or gallops                              could be recommended.
CHEST:    Clear to auscultation and percussion                                   • Consider discontinuing Titralac Plus® because of its pos
ABD:      Normal bowel sounds and mild epigastric tenderness                          sible contribution to his constipation. If an antacid is
RECT:     Non-tender; black melenic stool found in rectal vault                       desired, a product containing both magnesium and alu
EXT:      Normal range of motion                                                      minum to minimize bowel function changes may be
Labs:     sodium 140 mEq/L (135-147 mEq/L), potassium 4.2                             recommended.
          Eq/L (3.5-5 mEq/L) chloride 104 mEq/L (95-105
          mEq/ L), carbon dioxide 26 mEq/L (22-28 mEq/L),                   6.   What pharmacotherapeutic alternatives are available to treat
          BUN 10 mg/dL (8-18 mg/dI), serum creatinine 1.0                        JB?
          mg/dL (0.6-1.2 mg/dl), glucose 100 mg/dL (70-110                       • H. pylori eradication therapy is needed. Selection of
          mg/dl); calcium 9.6 mg/dl (8.8-10 mg/dl), magnesium                        specific regimen should be based on cost effectiveness
          2.0 mEq/L (1.6-2.4 meq/L) , phosphorus 4.0 mg/dL                           and JB's compliance to medication therapy. See Tables II
          (2.5-5 mg/dl), albumin 5.0 g/dL (4-6 g/dl),                                and III and Figure 5.
          hemoglobin 15.2 g/dL (14-18 g/dL), hematocrit 48%                 7.   Design a pharmacotherapeutic regimen for JB.
          (39%-49%), MCV91 cuu (76-100 cuu), platelets                           • Since JB is not allergic to any medications, an effective
          310,000 (150,000-450,000), WBC 7,500 (5,000-                               combination antibiotic regimen with an antisecretory
          10,000), serum iron 95 mcg/dL (80-180 mcg/dL).                             agent is preferred (See Table III and Figure 5). It is also
EGD:      Two days after the initial clinic visit an EGD was                         important to ascertain information from the patient con
          performed and revealed a 4-mm ulcer in the wall of the                     cerning prior antibiotic use and adherence to medication
          duodenum (Figure 3). The ulcer base was clear and                          therapy.
          free of blood. Mild inflammation of the antrum and                     • Discontinue aspirin use. If pain relief is needed, acetami
          the stomach was noted and biopsied.                                        nophen may be an appropriate alternative.
CLO-Test: Abundant Helicobacter pylori-like organisms.                           • Please include the non-pharmacologic recommendations
                                                                                     suggested earlier (see answer to Question 5). The need to
                                 ***                                                 be compliant to medication therapy should also be rein
                                                                                     forced to JB.
QUESTIONS AND ANSWERS:
                                                                            8.   In reference to JB's duodenal ulcer, list the two major moni
1. What signs, symptoms, and tests indicate the presence of                      toring parameters.
   peptic ulcer disease?                                                         • Relief of epigastric pain
    • Localized epigastric pain that appears to worsen at night                   • Resolution of complications (i.e., blood in stools).
         and decreases by ingesting food or Titralac Plus®.                       • For other possible monitoring parameters, refer back to
                                                                                      goals of treatment (see answer to Question 4).

                                           American Journal of Pharmaceutical Education Vol. 62, Summer 1998                                   203

								
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