5TH YEAR CLINICAL PHARMACY STUDENTS

Gastric Acid Anti-Secretory

Therapeutic Update
Practical Course Of Gastroenterology For Clinical
Pharmacy Students
Clinical Pharmacy Department
2/17/2013

The following statements are intended to describe the required basics and the last updates in therapeutics
issues of ant-secretory drugs and level of evidence being performed by associations assigned to these
updates. They are not intended to be an exhaustive list of all updates or clinical related issues.it is intended to
describe the general usage of these agents in gastric hypersecretory disorders and its consequences.

Antacids
A. Calcium-, aluminum-, and magnesium-based products are available OTC in
a wide variety of formulations (capsules, tablets, chewable tablets, and
suspensions).
B. Neutralizing acid and raising intragastric pH results in decreased activation
of pepsinogen and increased LES pressure; rapid onset of action but short
duration, necessitating frequent dosing
C. Some products (Gaviscon) contain the anti-refluxant alginic acid, which
forms a viscous layer on top of gastric contents to act as a barrier to reflux
(variable added efficacy).
D. Used as first-line therapy for intermittent (less than 2 times/week) symptoms
or as breakthrough therapy for those on PPI/H2RA therapy; not appropriate
for healing established esophageal erosions
E. Adverse reactions: Constipation (aluminum), diarrhea (magnesium),
accumulation of aluminum/ magnesium in renal disease with repeated
dosing
F. Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced
absorption because of increases in pH (ketoconazole, itraconazole, iron,
atazanavir, delavirdine, indinavir, nelfinavir) or increases in absorption
leading to potential toxicity (raltegravir, saquinavir)
Histamine-2-receptor antagonists
A. Reversibly inhibit Histamine-2-receptors on the parietal cell
B. All agents available as prescription and OTC products; a variety of
formulations available;generics exist for all prescription products
C. OTC H2RA products may be used for on-demand therapy for intermittent
mild-moderate GERD symptoms; preventive dosing before meals or
exercise is also possible for all agents. Higher prescription doses are often
required for more severe symptoms or for maintenance dosing. Prolonged
use may result in the development of tolerance and reduced efficacy
(tachyphylaxis).
D. Therapy with H2RAs is less efficacious than therapy with PPIs in healing
erosive esophagitis.

E. Adverse effects: Most are well tolerated. Central nervous system (CNS)
effects, such as headache, dizziness, fatigue, somnolence, and confusion, are
the most common. Elderly patients and those with reduced renal function are
more at risk. Prolonged cimetidine use is associated with rare development
of gynecomastia.
F. Drug interactions: May affect absorption of drugs dependent on lower
gastric pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine,
indinavir, and nelfinavir, or increases in absorption leading to potential
toxicity (raltegravir, saquinavir). Cimetidine also inhibits cytochrome P450
(CYP) enzymes 1A2, 2C9, 2D6, and 3A4. Warfarin, theophylline, and other
agents metabolized by these enzymes may be affected. Cimetidinem may
also compete with medications and creatinine for tubular secretion in the
kidney.

Proton pump inhibitors

A. Irreversibly inhibit the final step in gastric acid secretion; greater degree of
acid suppression achieved and typically longer duration of action than
H2RAs
B. Most effective agents for short- and long-term management of GERD, as
well as for management of erosive disease (Aliment Pharmacol Ther 2003;18:55968)
C. Most costly agents: Omeprazole and lansoprazole now available as a generic
prescription- strength product and OTC. The OTC products are considered
safe and effective for intermittent short-term (2 weeks) use in patients with
typical heartburn symptoms. Longterm use of OTC products should be
discussed with prescriber to prevent loss of followup or to assess for
potential undertreatment (Digestion 2009;80:22634). Pantoprazole and
esomeprazole are available in intravenous formulations.
D. Most effective when taken orally before meals; for divided dosing, give
evening dose before evening meal instead of at bedtime

E. Alternative administration

F. Adverse reactions: Overall, well tolerated; possible adverse effects include

headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not
associated with significant increases in endocrine neoplasia or symptomatic
vitamin B12 deficiency.(( the most important part at all))
1. A cohort study of 364,683 users of both PPIs and H2RAs found an
elevated risk of community-acquired pneumonia with these agents.
The adjusted relative risk of pneumonia was 1.89 (95% confidence
interval [CI], 1.362.62) with PPI use and 1.63 (95% CI, 1.072.48)
for H2RA use. Patients at risk of community-acquired pneumonia
include the immunocompromised, the elderly, children, and those
with asthma or chronic obstructive pulmonary disease. Acid
suppression should be used for these patients only if necessary and
only at the lowest possible dose (CMAJ 2011; 183:310.)
2. A recent large prospective cohort study of hospitalized patients
revealed an increased risk of hospital-acquired pneumonia in

nonventilated patients who were prescribed PPIs (OR = 1.3; 95% CI,
1.11.4) (JAMA 2009;301:21208).
3. Another recent study revealed a higher incidence of fracture in
patients receiving higher doses of PPIs for longer durations (OR =
1.44; 95% CI, 1.31.59) (Am J Gastroenterol 2012; 107:1361).This
may be attributable to reductions in the absorption of calcium in
patients receiving potent acid suppression or, possibly, interference
with osteoclast function.
4. New U.S. Food and Drug Administration (FDA) labeling for PPIs as
of May 2010 stating that PPIs may increase the risk of hip and spine
fracture(www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInfor
mationforPatientsandProviders/ucm213206.htm#SafetyAnnouncemen
t). The 2008 AGA guidelines cite insufficient evidence to recommend
bone density screening or calcium supplementation because of PPI
use. Screening for osteoporosis in populations at risk, such as the
elderly, is recommended regardless of PPI use.
5. Recent FDA warning regarding development of C. difficile infection.
http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm2910
58.html- (Am J Gastroenterol 2012; 107:1011.)
I. Magnitude of increase risk reported to be RR 1.4-2.75.
II. Recommendations include evaluating patients for C. difficle
infection if diarrhea does not improve in patients receiving
PPIs.
III. Patients should be advised to seek immediate care from a
healthcare professional if they experience watery stool that does
not go away, abdominal pain, and fever while taking PPIs.
IV. Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated.
V. Report adverse events involving PPIs to the FDA MedWatch
program
6. FDA warning in 2011 regarding risk of hypomagnesemia is patients
receiving PPIs (www.fda.gov/Drugs/DrugSafety/ucm245011.htm)
I. Most often associated with use greater than 1 year
II. May lead to tetany, arrhythmias, or seizures
III. May require discontinuation of PPIs and/or magnesium
supplementation.
IV. Consider checking a baseline serum magnesium concentration in
patients receiving diuretics or digoxin or requiring long-term PPI
use (Aliment Pharmacol Ther 2012; 36:405.).

G. Drug interactions: Drugs with pH-dependent absorption (ketoconazole,

itraconazole, protease inhibitors, etc.); omeprazole inhibits the metabolism
of diazepam through CYP2C19. Recent data suggest a reduced effectiveness
of clopidogrel through CYP2C19- mediated inhibition of conversion to
active metabolite by omeprazole and esomeprazole.
1. Recommendations are to avoid omeprazole, esomeprazole, and
cimetidine (CYP effects, also) in patients receiving clopidogrel. See
FDA letter at
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHu
manMedicalProducts/ucm190848.htm.
2. Guidelines (JACC 2010;56:116) on PPI/clopidogrel interaction
conclude that the magnitude of interaction is generally less than a
hazard ratio or odds ratio of 2. Findings from studies are inconsistent,
with most citing omeprazole as the most implicated. Although PPIs
should be used in patients at high risk of GI bleeding, H2RAs are less
effective but could possibly be used in patients at low risk of bleeding
or those whose symptoms are not severe enough to warrant PPI
therapy. Cimetidine should be avoided.
Sucralfate
A. Sucralfate (Carafate) is a sulfated polysaccharide, sucrose octasulfate,
complexed with aluminum hydroxide. It prevents acute chemically-induced
mucosal damage and heals chronic ulcers without altering gastric acid or
pepsin secretion or significantly buffering acid . Similar to aluminumcontaining antacids, sucralfate stimulates angiogenesis and the formation of
granulation tissue, possibly due to growth factor binding . Sucralfate also
binds to the injured tissue, thereby delivering growth factors and reducing
access to pepsin and acid.
B. Aluminum hydroxide mediates some of the actions of sucralfate, but the
sucrose octasulfate moiety may also have a role by contributing sulfhydryl
groups to reduce oxidant damage to epithelial cells. The binding of this
agent to the ulcer base is enhanced at a pH below 3.5, leading to the
recommendation that the drug be administered 30 to 60 minutes before
meals.
C. Sucralfate has been reported to suppress H. pylori and inhibit acid secretion
in infected patients with duodenal ulcers . No data are available to test the
relevance of this action by comparing ulcer healing in patients with H.
pylori-positive versus -negative duodenal ulcer.

D. Adverse effects Sucralfate has minimal adverse effects other than

possible aluminum toxicity . It can bind other drugs if taken simultaneously,
although the clinical consequences are minor.
E. Aluminum toxicity Significant absorption of aluminum occurs with
several antacid formulations and sucralfate . Daily consumption of 120
mmol of aluminum-containing antacid tablets for four weeks increases
serum and urinary aluminum levels . A therapeutic dose of sucralfate
contains about 0.8 g of aluminum and the aluminum absorption is
comparable to that seen with antacids .
1. Aluminum is readily excreted by normal kidneys; urinary levels are
elevated for one to three weeks after discontinuing therapy. By
comparison, significant aluminum retention occurs in patients with
renal failure, and may result in neurotoxicity and anemia following
treatment with either antacids or sucralfate . As a result, calcium
carbonate or acetate, rather than aluminum hydroxide is now the
primary agent used to bind dietary phosphate. Simultaneous
consumption of citrate enhances absorption of aluminum 50-fold in
patients with normal renal function, resulting in considerable
elevations in serum aluminum concentration . To avoid enhanced
aluminum absorption, especially in the setting of renal failure, it is
advisable to avoid combining antacids and probably sucralfate with
foods or other agents that contain citrate. If necessary to correct
metabolic acidosis, alkali should be given as sodium bicarbonate, not
sodium citrate.
2. The extent and consequences of aluminum deposition in tissues with
sustained use of either class of agents have not been defined; the
possibility of significant aluminum retention in the face of normal
renal function is remote. Aluminum deposits have been reported in
brain tissue in Alzheimer disease, but evidence points against
significant aluminum deposition in the brain or a role for this metal in
the pathogenesis of this disorder . Nevertheless, more rigorous
investigation of tissue aluminum is required in humans before firm
conclusions can be reached.
F. Aluminum hydroxide blocks intestinal absorption of phosphate; two weeks
of therapy with moderate doses can result in significant hypophosphatemia,
especially if the patient is on a low phosphate diet or is phosphate-depleted
for other reasons . Sucralfate also binds phosphate leading to similar

theoretical consequences; combining sucralfate and antacids can potentially

amplify these effects .
Bismuth
A. Several forms of bismuth were used for ulcer treatment long before the role
of H. pylori was recognized. Currently, colloidal bismuth subcitrate (CBS),
also known as tri-potassium di-citrato bismuthate (De-Nol), and bismuth
subsalicylate (BSS, Pepto-Bismol) are used in treatment of H. pylori
infection.
B. Bismuth subsalicylate is available in the United States either as PeptoBismol or Helidac, the latter in combination with tetracycline and
metronidazole. Helidac is approved in the United States for treatment of H.
pylori-associated duodenal ulcer. However, to more effectively cure H.
pylori and to ensure ulcer healing, it should be combined with twice daily
proton pump inhibitor treatment. Furthermore, the metronidazole dose in
Helidac is only 1 gram daily, which is too low to be effective in the face of
metronidazole resistance.
C. The most dramatic action of these bismuth salts is the suppression of H.
pylori . Bismuth is not effective in H. pylori-negative ulcers, suggesting the
healing efficacy of bismuth primarily reflects suppression of the infection.
However, there are numerous studies from the pre-H. pylori era suggesting
that bismuth also has other actions that may promote ulcer healing, including
the following:
1. Inhibition of peptic activity but not pepsin secretion
2. Bismuth from CBS may bind to ulcer craters
3. Macrophages, recruited to the edge of the ulcer crater in CBS-treated
rats, may promote healing
4. CBS may increase mucosal prostaglandin production, and mucus and
bicarbonate secretion
D. Bismuth does not inhibit or neutralize gastric acid.
E. The subsalicylate salt of bismuth has received too little study to determine
its antiulcer properties . In the colon, bismuth salts react with hydrogen
sulfide to form bismuth sulfide, which blackens the stools .
F. Adverse effects The primary concern with bismuth compounds is
bismuth intoxication; this was a problem primarily when bismuth subgallate
was used for prolonged periods at high doses. Bismuth absorption varies
with the specific form of bismuth; absorption is much greater with CBS than

with BSS or bismuth subnitrate . Coadministration of H2 receptor

antagonists increases bismuth absorption from CBS, but not from BSS or
bismuth subnitrate . Nevertheless, significant clinical toxicity has not been
reported in clinical trials with CBS or BSS . Bismuth should be avoided or
serum bismuth concentrations monitored in patients with renal failure [4].
G. The subsalicylate moiety in BSS is converted to salicylic acid and absorbed;
however, salicylate in the absence of the acetyl group does not inhibit
platelet function or appear to share the same high risk of aspirin for
gastrointestinal bleeding. However, the salicylate from bismuth subsalicylate
will contribute to serum salicylate levels and cause salicylate toxicity, and
combination with other salicylate products should therefore be avoided.
Prostaglandins
A. Prostaglandins, particularly of the E and I group, inhibit acid secretion by
selectively reducing the ability of the parietal cell to generate cyclic AMP in
response to histamine . Prostaglandins also enhance mucosal defense
mechanisms.
B. While several prostanoids have been tested for peptic ulcer healing, only
misoprostol (Cytotec) has been approved for use in the United States, and
not for ulcer healing but rather for prevention of NSAID-induced gastric
ulcer. Misoprostol is a 15-deoxy-15-hydroxy-16-methyl analogue of
prostaglandin E1. Topical action appears critical for prostaglandin action;
oral administration of misoprostol gives greater antisecretory efficacy and
fewer side effects than systemic administration.
C. Adverse effects The most frequent side effects of the E type prostanoids
are dose-dependent crampy abdominal pain and diarrhea . These side effects
interfere with compliance in many patients. The problem of misoprostolinduced diarrhea has been addressed in several ways:
1. Educate the patient to anticipate and manage mild, usually transient
cramps and diarrhea, but to stop the drug for more persistent or
troublesome problems
2. The patient should be instructed not to use concomitant cathartic
agents, to stop stool softeners unless absolutely necessary, and then to
reevaluate the need for these agents after several weeks of therapy
3. The dose of misoprostol should begin at 100 micrograms three to four
times daily, then increased to a maximal daily dose of 800
micrograms as tolerated

D. Lower doses of misoprostol have been used with some success for ulcer
prevention with a lower incidence of side effects .
E. Prostaglandins of the E group are uterotropic. Misoprostol has been given
with mifepristone to induce abortion . As a result, it is contraindicated in
women of childbearing potential who are not on contraception. All
patients should be informed of this risk to minimize the drug being
inadvertently given by the patient to a pregnant woman.
Promotility agents
A. Guidelines recommend against the use of metoclopramide as adjunctive
therapy or monotherapy in patients with both esophageal and
extraesophageal symptoms because the risk of adverse effects
(extrapyramidal symptoms [EPS]) or tardive dyskinesia) outweighs the
benefit (grade D). Metoclopramide now has black box warning for Tardive
Dyskinesia.
B. Work through cholinergic mechanisms to facilitate increased gastric
emptying.
C. Metoclopramide: Dopamine antagonist; needs to be dosed several times a
day; associated with many adverse effects such as dizziness, fatigue,
somnolence, drowsiness, EPS, and hyperprolactinemia. New 5- and 10-mg
ODT formulations (metoclopramide [Metozolv ODT]) are now available.
Indications for GERD and diabetic gastroparesis
D. Bethanechol: Cholinergic agonist; poorly tolerated because of adverse
effects such as diarrhea, blurred vision, and abdominal cramping; may also
increase gastric acid production
E. Cisapride: Available only on a restricted basis for patients whose other
therapies have failed; cisapride was withdrawn from the market initially
because of cardiac arrhythmia (torsades de pointes) when used in
combination with drugs inhibiting CYP3A4.