2. • Drugs Used to Treat Peptic Ulcer Disease and
Gastroesophageal Reflux Disease
• The two main causes of peptic ulcer disease are
1. infection with gram-negative Helicobacter pylori and
2. the use of non-steroidal anti-inflammatory drugs (NSAIDs).
3. Increased hydrochloric acid (HCl) secretion and inadequate
mucosal defense against gastric acid also play a role.
Treatment approaches include:
1) eradicating the H. pylori infection,
2) reducing secretion of gastric acid with the use of PPIs or H2
receptor antagonists, and/or
3) Providing agents that protect the gastric mucosa from
damage, such as misoprostol and sucralfate.
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3. A. Antimicrobial agents
• Patients with peptic ulcer disease (duodenal or gastric ulcers) who are
infected with H. pylori require antimicrobial treatment.
• Infection with H. pylori is diagnosed via endoscopic biopsy of the gastric
mucosa or various noninvasive methods, including serology, fecal antigen
tests, and urea breath tests.
• Eradication of H. pylori with various combinations of antimicrobial drugs
results in rapid healing of active ulcers and low recurrence rates.
• Currently, quadruple therapy of bismuth subsalicylate, metronidazole, and
tetracycline plus a PPI is a recommended first-line option.
• This usually results in a 90% or greater eradication rate.
• Triple therapy consisting of a PPI combined with amoxicillin
(metronidazole may be used in penicillin-allergic patients) plus
clarithromycin is a preferred treatment when rates of clarithromycin
resistance are low and the patient has no prior exposure to macrolide
antibiotics.
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4. B. H2 receptor antagonists
• Gastric acid secretion is stimulated by acetylcholine, histamine, and
gastrin.
• The receptor-mediated binding of acetylcholine, histamine, or
gastrin results in the activation of protein kinases, which in turn
stimulates the H+/K+-adenosine triphosphatase (ATPase) proton
pump to secrete hydrogen ions in exchange for K+ into the lumen of
the stomach.
• By competitively blocking the binding of histamine to H2 receptors,
these agents reduce the secretion of gastric acid.
• The four drugs used in the United States—
1. cimetidine ,
2. famotidine,
3. nizatidine,
4. ranitidine
• inhibit basal, food-stimulated, and nocturnal secretion of gastric
acid, reducing acid secretion by approximately 70%.
• Cimetidine was the first H2 receptor antagonist. However, its utility
is limited by its adverse effect profile and drug–drug interactions.
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6. 1. Actions
• The histamine H2 receptor antagonists act selectively on H2
receptors in the stomach, without effects on H1 receptors.
• They are competitive antagonists of histamine and are fully
reversible.
2. Therapeutic uses
• The use of these agents has decreased with the advent of PPIs.
a. Peptic ulcers
• All four agents are equally effective in promoting the healing of
duodenal and gastric ulcers.
• However, recurrence is common if H. pylori is present and the
patient is treated with these agents alone.
• Patients with NSAID-induced ulcers should be treated with PPIs,
because these agents heal and prevent future ulcers more
effectively than do H2 receptor antagonists.
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7. b. Acute stress ulcers
• These drugs are given as an intravenous infusion to prevent and
manage acute stress ulcers associated with high-risk patients in the
intensive care setting.
• However, because tolerance may occur with these agents, PPIs are
also used for this indication.
c. Gastroesophageal reflux disease
• H2 receptor antagonists are effective for the treatment of
heartburn or GERD.
• H2 receptor antagonists act by decreasing acid secretion; therefore,
they may not relieve symptoms of heartburn for up to 45 minutes.
• Antacids more quickly and efficiently neutralize stomach acid, but
their action is short lived.
• For these reasons, PPIs are now used preferentially in the
treatment of GERD, especially for patients with severe and frequent
heartburn.
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8. 3. Pharmacokinetics
• After oral administration, the H2 receptor antagonists
distribute widely throughout the body (including into breast
milk and across the placenta) and are excreted mainly in the
urine.
• Cimetidine, ranitidine, and famotidine are also available in
intravenous formulations.
• The half-life of these agents may be increased in patients with
renal dysfunction, and dosage adjustments are needed.
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9. 4. Adverse effects
• In general, the H2 receptor antagonists are well tolerated.
• However, cimetidine can have endocrine effects, such as
gynecomastia and galactorrhea (continuous release/discharge
of milk), because it acts as a nonsteroidal antiandrogen.
• Other central nervous system effects such as confusion and
altered mentalities occur primarily in elderly patients and
after intravenous administration.
• H2 receptor antagonists may reduce the efficacy of drugs that
require an acidic environment for absorption, such a
ketoconazole.
• Cimetidine inhibits several cytochrome P450 isoenzymes and
can interfere with the metabolism of many drugs, such as
warfarin, phenytoin, and clopidogrel.
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C. Inhibitors of the H+/K+-ATPase proton pump
• The PPIs bind to the H+/K+-ATPase enzyme system (proton
pump) and suppress the secretion of hydrogen ions into the
gastric lumen.
• The membrane-bound proton pump is the final step in the
secretion of gastric acid.
The available PPIs include :
• omeprazole,
• esomeprazole,
• lansoprazole,
• pantoprazole,
• rabeprazole ,
• Dexlansoprazole
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1. Actions
• These agents are prodrugs with an acid-resistant enteric
coating to protect them from premature degradation by
gastric acid.
• The coating is removed in the alkaline duodenum, and the
prodrug, a weak base, is absorbed and transported to the
parietal cell.
• There, it is converted to the active drug and forms a stable
covalent bond with the H+/K+-ATPase enzyme.
• It takes about 18 hours for the enzyme to be resynthesized,
and acid secretion is inhibited during this time.
• At standard doses, PPIs inhibit both basal and stimulated
gastric acid secretion by more than 90%.
• An oral product containing omeprazole combined with sodium
bicarbonate for faster absorption is also available.
12. 2. Therapeutic uses
• The PPIs are superior to the H2 antagonists in suppressing
acid production and healing ulcers.
1. Thus, they are the preferred drugs for the treatment of
GERD, erosive esophagitis, active duodenal ulcer, and
pathologic hypersecretory conditions such as Zollinger-
Ellison syndrome.
2. PPIs reduce the risk of bleeding from ulcers caused by aspirin
and other NSAIDs and may be used for prevention or
treatment of NSAID-induced ulcers.
3. PPIs are also used for stress ulcer prophylaxis and
management.
4. Finally, PPIs are combined with antimicrobial regimens used
to eradicate H. pylori.
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13. 3. Pharmacokinetics
• These agents are effective orally.
• For maximum effect, PPIs should be taken 30 to 60 minutes
before breakfast or the largest meal of the day.
• Esomeprazole, lansoprazole, and pantoprazole are available
in intravenous formulations.
• Although the plasma half-life of these agents is only a few
hours, they have a long duration of action due to covalent
bonding with the H+/K+-ATPase enzyme.
• Metabolites of these agents are excreted in urine and feces.
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14. 4. Adverse effects
• The PPIs are generally well tolerated.
• PPIs may increase the risk of fractures, particularly if the duration of use is
1 year or greater.
• Prolonged acid suppression with PPIs (and H2 receptor antagonists) may
result in low vitamin B12 because acid is required for its absorption in a
complex with intrinsic factor.
• Elevated gastric pH may also impair the absorption of calcium carbonate.
• Calcium citrate is an effective option for calcium supplementation in
patients on acid suppressive therapy, since absorption of the citrate salt is
not affected by gastric pH.
• Diarrhea and Clostridium difficile colitis may occur in patients receiving
PPIs.
• Patients must be counseled to discontinue PPI therapy and contact their
physician if they have diarrhea for several days.
• Additional adverse effects may include hypomagnesemia and an increased
incidence of pneumonia.
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15. D. Prostaglandins
• Prostaglandin E, produced by the gastric mucosa, inhibits secretion
of acid and stimulates secretion of mucus and bicarbonate
(cytoprotective effect).
• A deficiency of prostaglandins is thought to be involved in the
pathogenesis of peptic ulcers.
• Misoprostol , an analog of prostaglandin E1, is approved for the
prevention of NSAID-induced gastric ulcers.
• Prophylactic use of misoprostol should be considered in patients
who take NSAIDs and are at moderate to high risk of NSAID-induced
ulcers, such as elderly patients and those with previous ulcers.
• Misoprostol is contraindicated in pregnancy, since it can stimulate
uterine contractions and cause miscarriage.
• Dose-related diarrhea is the most common adverse effect and limits
the use of this agent.
• Thus, PPIs are preferred agents for the prevention of NSAID-
induced ulcers.
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16. E. Antacids
• Antacids are weak bases that react with gastric acid to form water
and a salt to diminish gastric acidity.
• Because pepsin (a proteolytic enzyme) is inactive at a pH greater
than 4, antacids also reduce pepsin activity.
• Food delays stomach emptying, allowing more time for the antacid
to react and prolonging the duration of action.
• Commonly used antacids are combinations of salts of aluminum
and magnesium, such as aluminum hydroxide and magnesium
hydroxide [Mg(OH)2].
• Calcium carbonate [CaCO3] reacts with HCl to form CO2 and CaCl2
and is also a commonly used preparation.
• Systemic absorption of sodium bicarbonate [NaHCO3] can produce
transient metabolic alkalosis and produce a significant sodium load.
Therefore, this antacid is not recommended.
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17. 2. Therapeutic uses
• Antacids are used for symptomatic relief of peptic ulcer
disease, heartburn, and GERD.
• They should be administered after meals for maximum
effectiveness.
3. Adverse effects
• Aluminum hydroxide tends to cause constipation, whereas
magnesium hydroxide tends to produce diarrhea.
• Preparations that combine these agents aid in normalizing
bowel function.
• Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) is
usually not a problem in patients with normal renal function;
however, accumulation and adverse effects may occur in
patients with renal impairment.
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18. III. Drugs Used to Control Chemotherapy-Induced Nausea and
Vomiting (CINV)
• Nausea and vomiting occur in a variety of conditions (for
example, motion sickness, pregnancy, and GI illnesses, and
chemotherapeutic agents)) and are always unpleasant for the
patient.
• Nearly 70% to 80% of patients who undergo chemotherapy
experience nausea and/or vomiting.
• Uncontrolled vomiting can produce dehydration, profound
metabolic imbalances, and nutrient depletion.
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19. A. Mechanisms that trigger vomiting
• Two brainstem sites have key roles in the vomiting reflex pathway.
1. The chemoreceptor trigger zone (CTZ) is located in the area
postrema (a circumventricular structure at the caudal end of the
fourth ventricle) in medulla.
• It is outside the blood–brain barrier.
• Thus, it can respond directly to chemical stimuli in the blood or
cerebrospinal fluid.
2. The second important site, the vomiting center, which is located in
the lateral reticular formation of the medulla, coordinates the
motor mechanisms of vomiting.
• The vomiting center also responds to afferent input from the
vestibular system, the periphery (pharynx and GI tract), and higher
brainstem and cortical structures.
• The vestibular system functions mainly in motion sickness.
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20. B. Emetic actions of chemotherapeutic agents
• Chemotherapeutic agents can directly activate the medullary
CTZ or vomiting center.
• Several neuroreceptors, including dopamine receptor type 2
and serotonin type 3 (5-HT3), play critical roles.
• Chemotherapeutic drugs can also act peripherally by causing
cell damage in the GI tract and by releasing serotonin from
the enterochromaffin cells of the small intestine.
• Serotonin activates 5-HT3 receptors on vagal and splanchnic
afferent fibers, which then carry sensory signals to the
medulla, leading to the emetic response.
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21. C. Antiemetic drugs
• Anticholinergic drugs, especially the muscarinic receptor
antagonist scopolamine and H1-receptor antagonists, such as
dimenhydrinate, meclizine, and cyclizine, are very useful in
motion sickness but are ineffective against substances that act
directly on the CTZ.
• The major categories of drugs used to control CINV include the
following:
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22. 1. Phenothiazines
• Phenothiazines, such as promethazine and
prochlorperazine, act by blocking dopamine
receptors in the CTZ.
• Prochlorperazine is effective against low or
moderately emetogenic chemotherapeutic agents
(for example, fluorouracil and doxorubicin).
• Although increasing the dose improves antiemetic
activity, adverse effects are dose limiting.
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23. 2. 5-HT3 receptor blockers
• The 5-HT3 receptor antagonists include
• dolasetron , granisetron , ondansetron, and palonosetron.
• These agents selectively block 5-HT3 receptors in the periphery
(visceral vagal afferent fibers) and in the CTZ.
• This class of agents is important in treating CINV, because of their
superior efficacy and longer duration of action.
• These drugs can be administered as a single dose prior to
chemotherapy (intravenously or orally) and are efficacious against
all grades of emetogenic therapy.
• These agents are also useful in the management of postoperative
nausea and vomiting.
• 5-HT3 antagonists are extensively metabolized by the liver;
however, only ondansetron requires dosage adjustments in hepatic
insufficiency.
• Excretion is via the urine.
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24. 3. Substituted benzamides
• One of several substituted benzamides with antiemetic
activity, metoclopramide , is
1. effective at high doses against CINV,
2. preventing emesis in 30% to 40% of patients
3. reducing emesis in the majority of patients.
• Metoclopramide accomplishes this through inhibition of
dopamine in the CTZ.
• Adverse effects: Antidopaminergic including extrapyramidal
symptoms, limit long-term high-dose use.
• Metoclopramide enhances gastric motility (prokinetic) and is
useful for patients with gastroparesis.
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25. IV. Antidiarrheals
• Increased motility of the GI tract and decreased
absorption of fluid are major factors in diarrhea.
Antidiarrheal drugs include;
• Anti-motility agents,
• Adsorbents,
• and drugs that modify fluid and electrolyte transport
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26. A. Antimotility agents
Two drugs that are widely used to control diarrhea are
diphenoxylate
loperamide .
• Both are analogs of meperidine and have opioid-like actions
on the gut.
• They activate presynaptic opioid receptors in the enteric
nervous system to inhibit acetylcholine release and decrease
peristalsis.
• At the usual doses, they lack analgesic effects.
• Loperamide is used for the general treatment of acute
diarrhea, including traveler’s diarrhea.
• Because these drugs can contribute to toxic megacolon, they
should not be used in young children or in patients with
severe colitis.
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27. B. Adsorbents
• Adsorbent agents, such as”
• aluminum hydroxide and methylcellulose, are used
to control diarrhea.
• Presumably, these agents act by adsorbing intestinal
toxins or microorganisms and/or by coating or
protecting the intestinal mucosa.
• They are much less effective than antimotility agents,
and they can interfere with the absorption of other
drugs.
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28. C. Agents that modify fluid and electrolyte transport
• Bismuth subsalicylate, used for prevention and
treatment of traveler’s diarrhea, decreases fluid
secretion in the bowel.
• Its action may be due to its salicylate component as
well as its coating action.
• Adverse effects may include black tongue and black
stools.
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29. V. Laxatives
• Laxatives are commonly used in the treatment of
constipation to accelerate the motility of the bowel,
soften the stool, and increase the frequency of bowel
movements.
• Laxatives increase the potential for loss of pharmacologic
effect of poorly absorbed, delayed acting, and extended-
release oral preparations by accelerating their transit
through the intestines.
• They may also cause electrolyte imbalances when used
chronically.
• Many of these drugs have a risk of dependency for the
user.
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30. A. Irritants and stimulants
1. Senna
• This agent is a widely used stimulant laxative.
• Its active ingredient is a group of sennosides, a natural
complex of anthraquinone glycosides.
• Taken orally, senna causes evacuation of the bowels within 6
to 12 hours.
• It also causes water and electrolyte secretion into the bowel.
• It is useful in treating opioid-induced constipation.
2. Bisacodyl
• Available as suppositories and enteric-coated tablets,
bisacodyl is a potent stimulant of the colon.
• It acts directly on nerve fibers in the mucosa of the colon.
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31. 3. Castor oil (stimulant)
• This agent is broken down in the small intestine to
ricinoleic acid, which is very irritating to the stomach and
promptly increases peristalsis.
• Pregnant patients should avoid castor oil because it may
stimulate uterine contractions.
• Use of castor oil is generally not recommended due to
poor palatability and potential for GI adverse effects.
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32. B. Saline and osmotic laxatives
• Lactulose is a semisynthetic disaccharide sugar that acts as
an osmotic laxative.
• It cannot be hydrolyzed by GI enzymes.
• Oral doses reach the colon and are degraded by colonic
bacteria into lactic, formic, and acetic acids.
• This increases osmotic pressure, causing fluid accumulation,
colon distension, soft stools, and defecation.
• Lactulose is also used for the treatment of hepatic
encephalopathy, due to its ability to reduce ammonia levels.
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