Drugs for Peptic
Ulcer Disease
Chapter 81
Peptic Ulcer Disease
• Definition
• Group of upper gastrointestinal (GI) disorders
• Degrees of erosion of the gut wall
• Severe erosion can be complicated by hemorrhage and perforation
• Cause
• Imbalance between mucosal and aggressive factors
2
• FIG. 81.1 The relationship
of mucosal defenses and
aggressive factors to health
and peptic ulcer disease.
When aggressive factors
outweigh mucosal defenses,
gastritis and peptic ulcers
result. NSAIDs, Nonsteroidal
antiinflammatory drugs.
Pathogenesis of Peptic Ulcers
• Defensive factors
• Mucus
• Secreted cells of the GI mucosa
• Forms a barrier to protect underlying cells from acid and pepsin
• Bicarbonate
• Secreted by epithelial cells of stomach and duodenum
• Most remains trapped in mucous layer to neutralize hydrogen ions that penetrate the mucus
• Blood flow
• Poor blood flow can lead to ischemia, cell injury, and vulnerability to attack
• Prostaglandins
• Stimulate the secretion of mucus and bicarbonate which helps maintain submucosal blod
flow, suppresses secrtion of gastric acid
4
Pathogenesis of
Peptic Ulcers
• Aggressive factors
• Helicobacter pylori, also known as H. pylori
• Gram-negative bacillus that can colonize the
stomach and duodenum
• Lives between epithelial cells and the mucous
barrier
• Escapes destruction by acid
• Can remain in the GI tract for decades
• Half of the world is infected, but most people
do not develop symptomatic peptic ulcer
disease (PUD)
This Photo by Unknown Author is licensed under CC BY
5
Pathogenesis of
Peptic Ulcers
• 60% to 75% of patients with PUD have H. pylori
infection
• H. pylori may also promote gastric cancer
• Duodenal ulcers are much more common
among people with H. pylori infection than
among people who are not infected
• Eradication of the bacterium promotes healing
of the PUD and minimized recurrence of PUD
6
H. pylori-Positive Gastritis in Conventional White Light Imaging
(WLI). A, diffuse redness of gastric mucosa; B, spotty hemorrhage at
fundus (arrow); C, enlarged gastric folds
Pathogenesis of Peptic Ulcers
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Inhibit the biosynthesis of prostaglandins
Reduce blood flow, mucus, and bicarbonate
Gastric acid
Causes ulcers directly by injuring cells of the GI
mucosa and indirectly by activating pepsin
Increased acid alone does not increase ulcers but is
a definite factor in PUD
Zollinger-Ellison syndrome –caused by a tumor that
secretes gastrin a hormone that stimulates gastric
acid production- rare disorder seen in only 0.1% of
duodenal ulcers
Pepsin
Proteolytic enzyme in gastric juice
Smoking
Delays ulcer healing and increases risk for
recurrence
Pathogenesis of Peptic Ulcers
• Summary of ulcer development
• Infection with H. pylori is the most common cause of gastric and duodenal ulcers
• Additional factors must be involved; 50% harbor H. pylori,
but only 10% develop PUD
• Second most common cause
• NSAIDs
9
Goals of drug therapy
Overview
of
Treatment
• Alleviate symptoms
• Promote healing
• Prevent complications
• Prevent recurrence
Drugs do not alter the disease
process; they create conditions
conducive to healing
10
Classes of Antiulcer Drugs- 5 major groups
• Antibiotics
• Antisecretory agents
• Mucosal protectants
• Antisecretory agents that enhance mucosal defenses
• Antacids
Drugs act in three basic ways to promote ulcer healing. Specifically, they can (1) eradicate
H. pylori (antibiotics do this), (2) reduce gastric acidity (antisecretory agents, misoprostol,
and antacids do this), and (3) enhance mucosal defenses (sucralfate and misoprostol do
this).
11
Drug
Selection:
H. pylori–
Associated
Ulcers
Antibiotics
• Should be given to all
patients with
gastric/duodenal ulcers and
documented H. pylori
infection
Antisecretory agents
12
Prophylaxis
Drug
Selection:
NSAIDInduced
Ulcers
• Risk factors for ulcer development: Age over 60
years, history of ulcers, high-dose NSAID therapy
• Proton pump inhibitors (PPIs) are preferred (eg,
omeprazole)
• Misoprostol is also effective but can cause diarrhea
Treatment
• Histamine blockers and PPIs (eg, omeprazole) are
preferred
• Antacids, sucralfate, and histamine2 receptor
blockers are not recommended
• Discontinue NSAIDs if possible
Evaluation of treatment
13
Pepsin
• Proteolytic enzyme that can contribute to ulcer formation; it promotes ulcers
by breaking down protein in the gut wall
• Activity of pepsin is pH dependent; drugs that elevate gastric pH (eg,
antacids, histamine2 antagonists, PPIs) can cause peptic activity to
increase, thereby enhancing pepsin’s destructive effects
• To avoid activation of pepsin, drugs that reduce acidity should be
administered in doses sufficient to raise the gastric pH above 5
14
Nondrug Therapy
• Diet
• Traditional “ulcer diet” does not
accelerate healing
• No convincing evidence indicates
that caffeinated beverages
promote ulcers or delay healing
• Change in eating pattern to five
or six small meals a day reduces
pH fluctuations
• Avoid smoking, aspirin, other NSAIDs,
and alcohol
• Stress reduction
15
Monitor for relief of pain
Evaluation
of Therapy
• Keep in mind: Cessation of pain and
disappearance of ulcer rarely coincide
• Pain may subside before complete healing
or may continue after healing
Radiologic or endoscopic
examination of ulcer site
H. pylori tests
16
H. pylori Tests
• Noninvasive
• Breath test-patients are given radiolabeled
urea. If H. pylori is present, the urea is
converted to carbon dioxide and ammonia;
radiolabeled carbon dioxide can then be
detected in the breath
• Serologic test-evaluated for antibodies
to H. pylori.
• Stool test- samples evaluated for presence
of H. pylori antigens.
• Invasive
• Endoscopic specimen obtained and
evaluated
• Stained and viewed under microscope
to see if H. pylori is present
• Assayed for presence of urease (a
marker enzyme for H. pylori)
• Cultured and then assayed for
presence of H. pylori
17
H. pylori Treatment
• Minimum of two antibiotics prescribed (up to three may be used) to reduce
risk of developing resistance
• Amoxicillin
• Clarithromycin
• Bismuth compounds
• Tetracycline
• Metronidazole
• Tinidazole
18
Antibiotic Regimen
Clarithromycin,
amoxicillin, bismuth,
metronidazole, and
tetracycline
None is effective
alone
If these drugs are
used alone, the risk
of resistance
developing increases
19
Clarithromycin [Biaxin]
• Suppresses growth of H. pylori by inhibiting protein synthesis
• In the absence of resistance, treatment is highly effective
• Unfortunately, rate of resistance is rising, exceeding 20% in some areas
• Most common side effects
• Nausea
• Diarrhea
• Distortion of taste
20
Amoxicillin
•
•
•
•
H. pylori is highly sensitive to amoxicillin
Rate of resistance is low, only about 3%
Amoxicillin kills bacteria by disrupting cell wall
Antibacterial activity is highest at a neutral pH and thus can be enhanced by
reducing gastric acidity with an antisecretory agent (eg, omeprazole)
• Most common side effect is diarrhea
21
Bismuth Compounds
• Act topically to disrupt the cell wall of H. pylori, causing lysis and death
• Also may inhibit urease activity and may prevent H. pylori from adhering to
the gastric surface
• Can impart a harmless black coloration to the tongue and stool
• Patient teaching
• Long-term therapy: Possible risk of neurologic injury
22
Tetracycline
• Inhibitor of bacterial protein
synthesis
• Highly active against H. pylori
• Resistance is rare (less than 1%)
• Do not use in pregnant patients
and young children because
tetracycline can stain developing
teeth
23
Metronidazole
[Flagyl]
• Very effective against sensitive strains
of H. pylori
• Over 40% of strains are now resistant
• Most common side effects are nausea
and headache
• Avoid alcohol: Disulfiram-like reaction
can occur if metronidazole is used with
alcohol
• Avoid use during pregnancy
24
​Tinidazole
[Tindamax]
• Very similar to metronidazole
• Has the same adverse effects
and interactions
• Can cause a disulfiram-like
reaction
• Do not combine with alcohol
25
Goal: Minimize emergence of resistance;
guidelines recommend using at least
two antibiotics, preferably three
​Antibiotic
Regimens
Antisecretory agent: PPI or histamine2
receptor antagonist (H2RA) also should
be used
Eradication rates are good with a 10-day
course and slightly better with a 14-day
course
26
Cimetidine [Tagamet]
Histamine2
Receptor
Antagonists
Ranitidine [Zantac]
Famotidine [Pepcid]
Nizatidine [Axid]
27
Histamine2
Receptor
Antagonists
(H2RAs)
First-choice drugs for treating
gastric and duodenal ulcers
Promote healing by suppressing
secretion of gastric acid
All four are equally effective
Serious side effects are
uncommon
28
Cimetidine
[Tagamet]
• Pharmacokinetics
• Absorption is slowed if taken
with meals
• Crosses the blood-brain
barrier with difficulty
• May cause some CNS side
effects
29
Mechanism
of Action
• FIG. 81.2 A model of the regulation
of gastric acid secretion showing
the actions of antisecretory drugs
and antacids.
Production of gastric acid is stimulated
by three endogenous compounds: (1)
acetylcholine (ACh) acting at
muscarinic (M) receptors; (2) histamine
(Hist) acting at histamine2 (H2)
receptors; and (3) gastrin (Gast) acting
at gastrin (G) receptors. As indicated,
all three compounds act through
intracellular messengers, either
calcium (Ca++) or cyclic AMP (cAMP),
to increase the activity of H+,K+–
adenosine triphosphatase (ATPase),
the enzyme that actually produces
gastric acid. Prostaglandins (PG)
decrease acid production, perhaps by
suppressing production of intracellular
cAMP. The actions of H2 receptor
antagonists (H2RAs), proton pump
inhibitors (PPIs), and other drugs are
indicated. P, Prostaglandin receptor.
Cimetidine [Tagamet]
• Therapeutic uses
• Gastric and duodenal ulcers
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome only with high doses which significant
adverse effects
• Aspiration pneumonitis
• Heartburn, acid indigestion, sour stomach
31
Adverse effects
Cimetidine
[Tagamet]
• Antiandrogenic effects
• CNS effects
• Pneumonia
• IV bolus: Can cause hypotension and
dysrhythmias
Drug interactions
• Warfarin, phenytoin, theophylline, lidocaine
• Antacids can reduce absorption of cimetidine
• Cimetidine and antacids should be
administered at least 1 hour apart
32
Has many of the properties of
cimetidine
Ranitidine
[Zantac]
• More potent, fewer adverse effects,
fewer drug interactions than cimetidine
Adverse effects
• Significant ones are uncommon
• Does not bind to androgen receptors
• Elevation of gastric pH may increase risk
of pneumonia
33
Ranitidine [Zantac]
• Therapeutic uses
• Short-term treatment of gastric/duodenal ulcers
• Prophylaxis of recurrent duodenal ulcers
• Treatment of Zollinger-Ellison syndrome and hypersecretory states
• Treatment of GERD
34
Actions similar to those of ranitidine
Therapeutic uses
Famotidine
[Pepcid]
• Short-term treatment of gastric/duodenal ulcers
• Prophylaxis of recurrent duodenal ulcers
• Treatment of Zollinger-Ellison syndrome and
hypersecretory states
• Treatment of GERD
• Over-the-counter (OTC): Treatment of heartburn, acid
indigestion, sour stomach
• Adverse effects
• No antiandrogenic effects because it does not bind to
androgen receptors
• Possible increased risk for pneumonia caused by elevation
of pH
35
Actions much like those of
ranitidine and famotidine
Nizatidine
[Axid]
Therapeutic uses
• Duodenal/gastric ulcers
• GERD, heartburn, acid
indigestion, sour stomach
36
Proton Pump Inhibitors
• Most effective drugs for suppressing secretion of gastric acid
• Therapeutic uses: Short term
• Gastric/duodenal ulcers
• GERD
• Well tolerated
• Selection of PPI is based on cost and prescriber’s preference
• Can increase the risk of serious adverse events, including fracture, pneumonia, acid
rebound, and possibly intestinal infection with Clostridium difficile
37
Omeprazole [Prilosec]
• First available PPI
• Actions and characteristics
•
•
•
•
Inhibits gastric secretion
Short half-life
Used for short-term therapy
Ulcer prophylaxis is indicated only for patients in intensive care units, and then only if they have
an additional risk factor, such as multiple trauma, spinal cord injury, or prolonged mechanical
ventilation (longer then 48 hours)
Adverse effects
Usually inconsequential with short-term use
Headache
GI effects
Pneumonia
Fractures
Hypomagnesemia
Rebound acid hypersecretion
C. difficile infection
Gastric cancer
38
Esomeprazole
[Nexium, Nexium IV]
• Nearly identical to omeprazole [Prilosec]
• Uses: Erosive esophagitis, GERD, duodenal ulcers associated with H. pylori
infection, prophylaxis of NSAID-induced ulcers
• Adverse effects: Headache, diarrhea, nausea, flatulence, abdominal pain, dry
mouth, pneumonia, hypomagnesemia, osteoporosis, fractures
39
Lansoprazole [Prevacid, Prevacid IV,
Prevacid 24 HR]
Very similar to
omeprazole
Adverse effects: Diarrhea,
abdominal pain, nausea,
pneumonia,
hypomagnesemia,
osteoporosis, fracture
40
Reduces gastric acidity by inhibiting gastric
H+,K+-ATPase
Dexlansoprazole
[Dexilant]
Uses: Treatment and maintenance of healing of
erosive esophagitis; treatment of symptomatic
GERD (heartburn)
Adverse effects: Diarrhea, abdominal pain,
nausea, vomiting, flatulence, upper respiratory
infection, hypomagnesemia, osteoporosis,
fractures
41
Much like omeprazole and
lansoprazole in actions, uses, and
adverse effects
Rabeprazole
Uses: H. pylori eradication, duodenal
ulcers, GERD, hypersecretory states
(eg, Zollinger-Ellison syndrome)
Mechanism of action: Reduces
gastric acidity by inhibiting gastric
H+,K+-ATPase
42
Similar to omeprazole and the other PPIs
Pantoprazole
[Protonix]
Uses: Treatment of GERD and
hypersecretory states
Adverse effects
• Oral: Diarrhea, headache, dizziness
• IV: Diarrhea, headache, nausea, dyspepsia,
injection-site reactions, including thrombophlebitis
and abscess
• Long-term use: Hypomagnesemia, osteoporosis,
fractures
43
Sucralfate [Carafate]
Other
Antiulcer
Drugs
Misoprostol [Cytotec]
Antacids
44
Creates a protective barrier against acid and
pepsin for up to 6 hours
Therapeutic uses
Sucralfate
[Carafate]
• Acute ulcers and maintenance therapy
Adverse effects
• Constipation (only 2% of patients)
Drug interactions
• Minimal
• Antacids may interfere with effects of sucralfate
45
Misoprostol [Cytotec]
• Therapeutic uses
• Only approved GI indication is prevention of gastric ulcers caused by long-term
NSAID therapy
• Adverse effects
• Most common: Dose-related diarrhea and abdominal pain
• Contraindicated during pregnancy: Category X
• Significant actions need to be taken to ensure that pregnancy does not occur
after therapy starts and that patient is not pregnant at therapy initiation
• Safety Alert Misoprostol In Pregnancy
• Misoprostol is contraindicated during pregnancy. The risk for use by pregnant women
clearly outweighs any possible benefits. Because prostaglandins stimulate uterine
contractions, the use of misoprostol during pregnancy has caused partial or complete
expulsion of the developing fetus.
46
Antacids
• React with gastric acid to produce neutral salts or salts of low acidity
• Reduce destruction of gut wall by neutralizing acid
• May also enhance mucosal protection by stimulating production of prostaglandins
• Except for sodium bicarbonate, antacids do not alter systemic pH
• Use with caution in patients with renal impairment
• Adverse effects
• Constipation: Aluminum hydroxide
• Diarrhea: Magnesium hydroxide
• Sodium loading
•
•
•
•
Drug interactions
Cimetidine
Ranitidine
Sucralfate
47
Antacid Families
Aluminum compounds
Magnesium compounds
Calcium compounds
Sodium compounds
48
Magnesium Hydroxide
[Milk of Magnesia]
• Rapid acting, high acid-neutralizing capacity (ANC),
produces long-lasting effects
• An antacid of choice
• Most prominent adverse effect is diarrhea
• Usually taken in combination with aluminum hydroxide, an
antacid that promotes constipation
• Avoided in patients with undiagnosed abdominal pain
• Frequently used as a laxative
• Use with caution in patients with renal failure
49
This Photo by Unknown Author is licensed under CC BY-SA-NC
Aluminum Hydroxide
• Relatively low ANC, slow acting
• Effects have long duration
• Rarely used alone
• Widely used in combination with magnesium hydroxide
• Caution: Significant amounts of sodium
• Constipation
• Drug interactions: Tetracyclines, warfarin, digoxin
50
Calcium Carbonate
Rapid acting, high ANC, effects have long duration
Acid rebound
Principal adverse effect: Constipation, which can be overcome by combining
calcium carbonate with a magnesium-containing antacid (eg, magnesium
hydroxide)
Eructation (belching) and flatulence
Low palatability
51
Sodium
Bicarbonate
• Useful for treating acidosis and
elevating urinary pH to promote
excretion of acidic drugs after
overdose
• Inappropriate for treating PUD:
Brief duration, high sodium
content, can cause alkalosis
• Eructation and flatulence
• Can exacerbate hypertension and
heart failure
This Photo by Unknown Author is licensed under CC BY-SA
• Can cause systemic alkalosis in
patients with renal impairment
52
Helidac
Combination
Packs
Pylera
Prevpac
53
Laxatives
Chapter 82
This Photo by Unknown Author is licensed under CC BY-SA-NC
Laxatives
• Used to ease or stimulate defecation
• Soften the stool
• Increase stool volume
• Hasten fecal passage through the intestine
• Facilitate evacuation from the rectum
• Misuse comes from misconceptions of what constitutes normal bowel function
55
Laxative Effect Versus
Catharsis
Laxative effect
• Production of soft, formed stool over 1 or more days
• Relatively mild
Catharsis
• Prompt, fluid evacuation of the bowel
• Fast and intense
Therefore, a laxative effect is slower and relatively mild,
whereas catharsis is relatively fast and intense.
56
Function of the Colon
Absorbs water and electrolytes
• Absorption of nutrients is minimal
• 1500 mL of fluid enters colon each day
• 90% of fluid is absorbed
Delayed transport through colon causes excessive fluid absorption and hard
stool
Frequency of bowel elimination varies widely (from 2 to 3 times/day to 2
times/wk)
57
Dietary Fiber
• Proper bowel function is highly
dependent on dietary fiber (bran is
best source)
• Benefits of fiber
• Absorbs water: Softens feces and
increases size
• Can be digested by colonic
bacteria, whose growth increases
fecal mass
• Low-fiber diet: Frequent cause of
constipation
58
One of the most common GI disorders
Constipation
• People seek medical help for constipation in the
United States at least 2.5 million times a year
• Hundreds of millions of dollars a year are spent
on laxatives
Constipation may be defined as:
• Hard stools, infrequent stools, excessive
straining, prolonged effort, sense of incomplete
evacuation, unsuccessful defecation
59
Obtain fresh stool sample
Empty bowel before treatment or procedure
Indications
for Laxative
Use
Expel dead parasites after treatment
Modify effluent from ileostomy or colostomy
Constipation (multiple causes, including pregnancy and
opioid use)
Prevent fecal impaction in bedridden patients
Remove poisons
60
Abdominal pain, nausea, cramps, or other symptoms of
appendicitis, regional enteritis, diverticulitis, or ulcerative
colitis
Acute surgical abdomen
Contraindications
to Laxative Use
Fecal impaction or bowel obstruction
Habitual use
Use with caution in pregnancy and lactation
61
Classification of Laxatives
• Bulk-forming laxatives
• Psyllium [Metamucil]
• Surfactant laxatives
• Docusate sodium [Colace]
• Stimulant laxatives
• Bisacodyl [Dulcolax]
• Osmotic laxatives
• Milk of magnesia (MOM)
62
Classification
of Laxatives:
Therapeutic
Effect
• Group I: Act rapidly (within 2 to 6 hours) and
give stool a watery consistency; useful for
preparing bowel for diagnostic procedures
or surgery
• Group II: Intermediate latency (6 to 12
hours); produce a semifluid stool
• Group III: Most frequently abused by the
general public; act slowly (1 to 3 days) to
produce a soft, formed stool; uses include
treating chronic constipation and preventing
straining at stool
63
Function similarly to dietary fiber: Swell
with water to form a gel that softens and
increases fecal mass
BulkForming
Laxatives
Preferred temporary treatment of
constipation
• Used for diverticulosis and irritable bowel syndrome
Adverse effects are minimal
• Esophageal obstruction
64
Surfactant
Laxatives
• Produce a soft stool several days after onset of
treatment
• Alter stool consistency by lowering surface
tension, which facilitates penetration of
water into feces
• May also act on intestinal wall to (1) inhibit
fluid absorption and (2) stimulate secretion
of water and electrolytes into intestinal
lumen; in this respect, surfactants resemble
stimulant laxatives
65
Two effects on bowel:
Stimulant
Laxatives
(e.g., bisacodyl, senna,
castor oil)
• Stimulate intestinal motility
• Increase amounts of water and electrolytes in
intestinal lumen
Widely used and abused
Legitimately used for opioid-induced
constipation and for constipation from slow
intestinal transit
66
Bisacodyl [Correctol, Dulcolax]
• Bisacodyl is unique among the stimulant laxatives in that it can be
administered by rectal suppository or by mouth.
• Oral bisacodyl acts within 6 to 12 hours. Tablets may be given at bedtime
to produce a response the next morning. Bisacodyl suppositories act
rapidly (in 15 to 60 minutes). Dosages for bisacodyl are shown in Table
82.4.
• Bisacodyl tablets are enteric coated to prevent gastric irritation.
Accordingly, patients should be advised to swallow them intact, without
chewing or crushing. Because milk and antacids accelerate dissolution of
the enteric coating, the tablets should be administered no sooner than
1 hour after ingesting these substances.
• Bisacodyl suppositories may cause a burning sensation; with continued
use, proctitis may develop. Accordingly, long-term use should be
discouraged.
Senna[Senokot, Ex-Lax]
is a plant-derived laxative that
contains anthraquinones as active
ingredients.
actions and applications of senna
are similar to those of bisacodyl.
Anthraquinones act on the colon to
produce a soft or semifluid stool in
6 to 12 hours. Systemic absorption
followed by renal secretion may
impart a harmless yellowish-brown
or pink color to the urine.
Castor Oil
• Castor oil is the only stimulant laxative that acts on the
small intestine. As a result, the drug acts quickly (in 2
to 6 hours) to produce a watery stool.
• The use of castor oil is limited to situations in which
rapid and thorough evacuation of the bowel is desired
(e.g., preparation for radiologic procedures).
• The drug is far too powerful for routine treatment of
constipation.
• Because of its relatively prompt action, castor oil should
not be administered at bedtime.
• The drug has an unpleasant taste that can be improved
by chilling and mixing with fruit juice.
Laxative salts (sodium phosphate, magnesium
hydroxide)
• Poorly absorbed salts that draw water into intestinal lumen; fecal
mass softens and swells, wall stretches, and peristalsis is stimulated
Osmotic
Laxatives
Low doses: Results in 6 to 12 hours
High doses: Results in 2 to 6 hours
Adverse effects
• Dehydration: Substantial water loss
• Acute renal failure
• Sodium retention: Exacerbated heart failure, hypertension, edema
70
Polyethylene Glycol (PEG) [MiraLax, GlycoLax, Peglax )
• Polyethylene glycol image] is an osmotic laxative used widely for chronic constipation.
Like the laxative salts, PEG is a nonabsorbable compound that retains water in the
intestinal lumen, causing the fecal mass to soften and swell.
• adverse effects are nausea, abdominal bloating, cramping, and flatulence. High doses
may cause diarrhea.
• For management of chronic constipation, PEG is superior to lactulose for relief of
abdominal pain and improvements in stool consistency and frequency per week,
although side effects are similar.
• recommended dosage is 17 gm once a day, dissolved in 4 to 8 ounces of water, juice,
soda, coffee, or tea. Bowel movement may not occur for another 2 to 4 days.
• products that contain PEG plus electrolytes can be used to cleanse the bowel before
colonoscopy and other procedures.
Other Laxatives
• Lubiprostone
• Selective chloride channel activator
• By activating (opening) chloride channels in epithelial cells lining the intestine,
lubiprostone (1) promotes secretion of chloride-rich fluid into the intestine and (2)
enhances motility in the small intestine and colon
• The result is spontaneous evacuation of a semisoft stool, usually within 24 hours
• Mineral oil: Mixture of indigestible and poorly absorbed hydrocarbons. Laxative action is
produced by lubrication. Mineral oil is especially useful when administered by enema to
treat fecal impaction.
• Adverse effects: Lipid pneumonia, anal leakage, and deposition of mineral oil in the liver.
72
Other Laxatives
• Glycerin suppository: Osmotic agent that softens and lubricates
hardened, impacted feces
• May also stimulate rectal contraction
• Evacuation occurs about 30 minutes after suppository insertion
• Useful for reestablishing normal bowel function after termination of chronic
laxative use
73
Bowel-Cleansing
Products for Colonoscopy
Allow for good visualization of the bowel
Types
• Sodium phosphate
• Hypertonic with body fluids
• Can cause dehydration and electrolyte disturbance
• Possibility of renal damage
• Polyethylene glycol (PEG) plus electrolytes (ELS)
• Isotonic with body fluids
• Requires ingestion of large volume of bad-tasting liquid
• Combination of sodium picosulfate, magnesium oxide, and citric acid
74
Polyethylene Glycol—
Electrolyte Solutions
• CoLyte, GoLytely
• Volume administered is huge,
typically 4 L. Patients must ingest
250 to 300 mL every 10 minutes
for 2 to 3 hours. With HalfLytely
and MoviPrep, the volume is cut
in half.
• Most common adverse effects
are nausea, bloating, and
abdominal discomfort.
75
This Photo by Unknown Author is licensed under CC BY-NC
Osmotic laxatives that draw water into
intestinal lumen, which softens and swells
fecal mass, which stretches intestinal wall to
stimulate peristalsis
Sodium
Phosphate
Products
Adverse effects: Nausea, bloating, abdominal
discomfort; risk of dehydration, electrolyte
disturbances, and kidney damage
Hyperphosphatemia, which can cause acute,
reversible renal damage and possibly chronic,
irreversible renal damage
76
Magnesium oxide/anhydrous citric acid/sodium
picosulfate [Prepopik] has been approved for
preparation for colonoscopy in adults.
Combination
Product
Adverse effects: Possible electrolyte and fluid
imbalances, renal impairment, seizures, and
arrhythmia secondary to electrolyte
abnormalities. Caution must be used in patients
with reduced renal function. The most common
adverse reactions are nausea, headache, and
vomiting.
77
Causes
Laxative
Abuse
• Misconception that bowel movements
must occur daily
• Can perpetuate their own use
• Bowel replenishment after evacuation can
take 2 to 5 days; often mistaken for
constipation
Consequences
• Diminished defecatory reflexes, leading to
further reliance on laxatives
• Electrolyte imbalance, dehydration, colitis
78
Other
Gastrointestinal
Drugs
Chapter 83
GI Drugs
• Antiemetics
• Antidiarrheals
• Drugs for irritable bowel
syndrome
• Drugs for inflammatory bowel
disease
80
Antiemetics
• Given to suppress nausea and vomiting
• Emetic response
• Complex reflex that occurs after activation of vomiting center in the medulla
oblongata
• Several types of receptors involved in emetic response:
• Serotonin, glucocorticoids, substance P, neurokinin1, dopamine, acetylcholine,
histamine
• Many antiemetics interact with one or more of the receptors
81
Several types of receptors
are involved in the emetic
response. Important among
these are receptors for
serotonin, glucocorticoids,
substance P, neurokinin1,
dopamine, acetylcholine,
and histamine. Many
antiemetics, including
ondansetron [Zofran],
dexamethasone, aprepitant
[Emend], prochlorperazine,
and dimenhydrinate, act by
blocking (or activating) one
or more of these receptors.
FIG. 83.1 The emetic response: stimuli, pathways, and receptors.
CTZ, Chemoreceptor trigger zone.
Granisetron, dolasetron, palonosetron
Serotonin
receptor
antagonists
Ondansetron [Zofran]
• First approved for chemotherapy-induced
nausea and vomiting (CINV)
• Also used to prevent nausea and vomiting
associated with radiotherapy and anesthesia
• Blocks type 3 serotonin receptors on afferent
vagal nerve
• More effective when used with
dexamethasone
• Adverse effects: Headache, diarrhea, dizziness,
prolonged QT interval, risk of torsades de
pointes
83
Antiemetics - Glucocorticoids
•
•
•
•
Unknown mechanism of action (MOA) as antiemetic
Methylprednisolone
Dexamethasone
Commonly used to suppress CINV; however, this is not an application
approved by the U.S. Food and Drug Administration (FDA)
• Effective alone and in combination with antiemetics
• dexamethasone and methylprednisolone are administered IV. Because
antiemetic use is intermittent and short term, serious side effects are absent.
84
Antiemetics
• Substance P/neurokinin1 antagonists
• Aprepitant
• Blocks neurokinin1-type receptors (for substance P) in the chemoreceptor trigger
zone (CTZ)
• Prevents postoperative nausea/vomiting and CINV
• Prolonged duration of action
• Adverse effects: Generally, well tolerated
• Drug interaction: CYP3A4, CYP2D6
85
AntiemeticsBenzodiazepines
• Lorazepam [Ativan]
• Used in combination
regimens to suppress CINV
• Three primary benefits:
• Sedation
• Suppression of
anticipatory emesis
• Production of
anterograde amnesia
86
This Photo by Unknown Author is licensed under CC BY
Antiemetics-Dopamine antagonists
• Phenothiazines: Prochlorperazine
• Block dopamine2 receptors in CTZ
• Surgery, cancer, chemotherapy, and toxins
• Use in children
• Side effects
• Extrapyramidal reactions
• Anticholinergic effects
• Hypotension and sedation
87
Antiemetics - Butyrophenones
• Haloperidol [Haldol] and droperidol
[Inapsine]
• Block dopamine2 receptors in CTZ
• Postoperative nausea/vomiting,
chemotherapy emesis, radiation
therapy, and toxins
• Side effects
• Similar to phenothiazines
• May cause prolonged QT
interval and fatal dysrhythmias
• Electrocardiogram (ECG)
before administration
88
Antiemetics
• Metoclopramide [Reglan]
• Blocks dopamine receptors in CTZ
• Postoperative nausea/vomiting, anticancer drug, opioids, toxins, radiation therapy
• Cannabinoids
• Dronabinol [Marinol] and nabilone [Cesamet]
• Related to marijuana
• Cancer Induced Nausea Vomiting CINV
• MOA with emesis unclear
• Potential for abuse and psychotomimetic effects
89
Three types of emesis:
Management of
ChemotherapyInduced Nausea
and Vomiting CINV
• Anticipatory
• Occurs before drugs are given
• Acute
• Onset within minutes to a few hours
• Delayed
• Onset 1 day or longer after drug administration
Antiemetics are more effective in preventing CINV
than in suppressing CINV in progress
Give before chemotherapy drugs
Monotherapy and combination therapy may be
needed
90
Nausea and
Vomiting of Pregnancy
• Hyperemesis gravidarum: Dehydration, ketonuria,
hypokalemia, and loss of 5% or more of body weight
• Nondrug measures
• First-line therapy consists of a two-drug combination:
Doxylamine plus vitamin B6
• Others: Prochlorperazine, metoclopramide, and
ondansetron; methylprednisolone may be tried as a
last resort, but only after 10 weeks’ gestation
91
Drugs for Motion
Sickness
• Scopolamine
• Muscarinic antagonist
• Side effects
• Dry mouth
• Blurred vision
• Drowsiness
92
Drugs for Motion
Sickness (Cont.)
• Antihistamines
• Dimenhydrinate, meclizine,
cyclizine
• Considered anticholinergics;
block receptors for acetylcholine
and histamine
• Side effects
• Sedation (H1 receptor
blocking)
• Dry mouth, blurred vision,
urinary retention,
constipation (muscarinic
receptor blocking)
93
Diarrhea
• Characterized by stools of excessive volume
and fluidity and increased frequency of
defecation
• Symptom of GI disease
• Causes
• Infection, maldigestion, inflammation,
functional disorders of the bowel
• Complications
• Dehydration and electrolyte depletion
94
Management
Diarrhea
• Diagnosis and treatment of underlying
disease
• Replacement of lost water and salts
• Relief of cramping
• Reducing passage of unformed stools
Two major groups of antidiarrheals
• Specific antidiarrheal drugs
• Nonspecific antidiarrheal drugs
95
Nonspecific
Antidiarrheal
Agents
• Opioids
• Most effective antidiarrheal agents
• Diphenoxylate, difenoxin, loperamide,
paregoric, and opium tincture
• Activate opioid receptors in GI tract
• Reduce intestinal motility
• Slow intestinal transit
• Allow more fluid to be absorbed
• Decrease secretion of fluid into small
intestine and increase absorption of fluid
and salt
• Most commonly used: Diphenoxylate [Lomotil]
and loperamide [Imodium]
96
Diphenoxylate [Lomotil]
Nonspecific
Antidiarrheal
Agents
• Formulated with atropine to discourage
abuse
• Opioid used only for diarrhea
• High doses can elicit typical morphinelike subjective responses
Loperamide
• Structural analog of meperidine
• Used to treat diarrhea and to reduce the
volume of discharge from ileostomies
• Little or no potential for abuse
97
Difenoxin
Paregoric
Nonspecific
Antidiarrheal
Agents
Opium tincture
Bismuth subsalicylate
Bulk-forming agents
Anticholinergic antispasmodics
98
General considerations
Management
of Infectious
Diarrhea
• Variety of bacteria and protozoa can be
responsible
• Infections are usually self-limited
• Many cases require no treatment
• Antibiotics should be used only when clearly
indicated: Salmonella, Shigella, Campylobacter,
or Clostridium infections
Traveler’s diarrhea
Escherichia coli: Usually self-limiting
Ciprofloxacin, norfloxacin
99
Most common disorder of GI tract
Irritable
Bowel
Syndrome
(IBS)
• Affects 10% to 15% of Americans
• Incidence in women is 3 times higher than in men
Characterized by cramping abdominal pain (may be severe) that
cannot be explained by structural or chemical abnormalities
May occur with diarrhea, constipation, or both
Considered IBS when symptoms have been present for 12 weeks
over the past year
100
Four groups of drugs historically used
Irritable
Bowel
Syndrome
(IBS)
• American College of Gastroenterology has
concluded there is no proof of clinical benefit for
most of these agents:
• Antispasmodics
• Bulk-forming agents
• Antidiarrheals
• Tricyclic antidepressants
Studies suggest that antibiotics or an acid
suppressant may be effective for some
patients
101
IBS-Specific
Drugs
• Alosetron [Lotronex]
• Potentially hazardous drug; approved for
women only
• GI toxicities can cause complicated
constipation, leading to perforation and
ischemic colitis
• Risk management program
• Drug interactions
102
• Lubiprostone [Amitiza]
• Approved for constipation-predominant IBS
(IBS-C) in women age 18 years or older
• Modest benefits
IBS-Specific
Drugs
• Tegaserod [Zelnorm]
• Short-term therapy of IBS-C and chronic
idiopathic constipation (CIC) in women
younger than age 55 years who are free of
cardiovascular (CV) disease
• Regulatory history
• Adverse effects
• Contraindications
103
Inflammatory Bowel
Disease (IBD)
• Caused by exaggerated immune response to normal bowel flora
• Crohn’s disease
• Characterized by transmural inflammation
• Usually affects terminal ileum (can affect all parts of GI
tract)
• Ulcerative colitis
• Inflammation of the mucosa and submucosa of the colon
and rectum
• May cause rectal bleeding
• May require hospitalization
104
This Photo by Unknown Author is licensed under CC BY-SA
Drugs for
IBD
• Not curative; may control disease process
• 5-Aminosalicylates (sulfasalazine; 5-ASA)
• Glucocorticoids (hydrocortisone)
• Immunosuppressants (azathioprine)
• Immunomodulators (infliximab)
• Antibiotics (metronidazole)
105
5-Aminosalicylates
• Sulfasalazine [Azulfidine]
• 5-ASA reduces inflammation; it also suppresses prostaglandin synthesis and
migration of inflammatory cells into affected region
• Most effective against acute episodes of mild to moderate ulcerative colitis
• Adverse effects
106
Glucocorticoids
• Budesonide
• Approved for mild to moderate Crohn’s disease that involves the ileum and
ascending colon
• Prolonged use of glucocorticoids can cause severe adverse effects, including adrenal
suppression, osteoporosis, increased susceptibility to infection, and a cushingoid
syndrome
107
Immunosuppressants
• Azathioprine [Imuran] and mercaptopurine [Purinethol]
• Induce and maintain remission in both ulcerative colitis and Crohn’s disease
• Onset of effects may be delayed for up to 6 months
• Reserved for patients who have not responded to traditional therapy
• Adverse effects are pancreatitis and neutropenia
108
Immunomodulators
• Infliximab [Remicade]
• Monoclonal antibody designed to neutralize tumor necrosis factor (TNF), a key
immunoinflammatory modulator
• Moderate to severe Crohn’s disease and ulcerative colitis
• Adverse effects
• Infusion reactions
109
Antibiotics
• Metronidazole [Flagyl] ciprofloxacin [Cipro]
• Crohn’s disease: Can help control symptoms
• Ulcerative colitis: Antibiotics largely ineffective
• Metronidazole [Flagyl]: Long-term therapy is required; prolonged use of high-dose
metronidazole poses risk of peripheral neuropathy
• Ciprofloxacin [Cipro]: Highly effective in patients with mild or moderate Crohn’s
disease
110
Prokinetic Agents
• Increase tone and motility of GI tract
• GERD, CINV, diabetic gastroparesis
• Metoclopramide [Reglan, Maxolon, Octamide]
• Blocks receptors for dopamine and serotonin in the CTZ
• Increases upper GI motility and suppresses emesis
• Cisapride [Propulsid]
• Suppress emesis and increase upper GI motility
• Metoclopramide [Reglan]
• Therapeutic uses
• PO: Diabetic gastroparesis and suppression of gastroesophageal reflux
• IV: Suppression of postoperative nausea and vomiting, suppression of CINV, facilitation of small bowel intubation,
and facilitation of radiologic examination of GI tract
• Adverse effects
• High-dose therapy: Sedation, diarrhea common
• Long-term high-dose therapy: Can cause irreversible tardive dyskinesia (TD)
111
Palifermin [Kepivance]
• First drug approved for decreasing oral mucositis (OM)
• Currently indicated only for patients with hematologic malignancies (can
stimulate proliferation of malignant cells of nonhematologic origin)
• Synthetic form of human keratinocyte growth factor (KGF)
• Stimulates proliferation, differentiation, and migration of epithelial cells
112
Pancreatic Enzymes
Deficiency of enzymes
compromises digestion
Pancrelipase: Pancreatic
enzyme for clinical use;
mixture of lipases,
amylases, and proteases
prepared from hog
pancreas
Adverse effects
Drug interactions
113
Drugs Used to Dissolve Gallstones
Chenodiol (chenodeoxycholic acid)
• Useful for radiolucent stones (not calcium)
• Increases production of bile acids
• Most successful in women with low cholesterol levels
Ursodiol (ursodeoxycholic acid)
• Does not increase bile acids
• Reduces cholesterol content of bile
• Gradual dissolution of stones
114
Anorectal Preparations
Symptomatic relief of hemorrhoids and other anorectal
disorders
• Local anesthetics
• Hydrocortisone
• Emollients
• Astringents
Multiple formulations available
115