GI Drugs

Dr. April Dawn Rallos-Lucero

 High-Yield Terms
Antiemetic
A drug that reduces nausea and vomiting
 High-Yield Terms
• Gastroparesis
Paralysis of the muscles of the stomach and possibly other parts of the
gastrointestinal tract due to damage to GI nerves or muscle
Common in advanced diabetes and advanced Parkinson disease
 High-Yield Terms
• Inflammatory Bowel Disease (IBD)
Inflammatory disorder involving irritation and ulceration of the colon and
rectum (ulcerative colitis) or the colon plus more proximal parts of the
gastrointestinal tract (Crohn’s disease)
• Irritable Bowel Syndrome
Disease of unknown origin characterized by episodes of abdominal
discomfort and abnormal bowel function (diarrhea, constipation, or
both)
 High-Yield Terms
• Prokinetic
A drug that promotes gastrointestinal motility

• Proton pump
The parietal cell H+/K+ ATPase that uses the energy of ATP to secrete
protons into the stomach; final common target of drugs that suppress acid
secretion
Drugs Used in Acid-Peptic Disease
 Acid-peptic disease

• A group of disorders involving erosion or ulceration of the

mucosal lining of the gastrointestinal tract

• Includes GERD, gastric and duodenal ulcers, nonulcer dyspepsia,

and stress-related gastritis
Gastroesophageal Reflux Disease (GERD)
• Esophageal irritation or inflammation due to reflux of stomach acid
• Also known as heartburn
 aka pyrosis; characterized by burning retrosternal discomfort that may move up and
down the chest like a wave
• It can be caused by a sustained or transient decrease in lower esophageal
sphincter tone
• Heartburn and regurgitation of sour material into the mouth are the
characteristic symptoms of GERD
 Peptic Ulcer Disease
• Encompasses both gastric and duodenal ulcers.
• Ulcers are defined as breaks in the mucosal surface >5 mm in size, with depth
to the submucosa
Although the pathogenesis of peptic ulcer disease is not
fully understood, several major causative factors are
recognized:
a) nonsteroidal anti- patients with duodenal ulcers

inflammatory drug (NSAID) c) increased hydrochloric acid

use
b) infection with gram-negative
Helicobacter pylori
- detectable in over 80% of
secretion
d) inadequate mucosal defense
against gastric acid
 Clinical Presentation

• Epigastric pain described as a

burning or gnawing discomfort

• The discomfort is also described as an

ill-defined, aching sensation or as
hunger pain.
 Clinical Presentation
• Typical pain pattern in DU
occurs 90 min to 3 h after a meal
frequently relieved by antacids or food
pain that awakes the patient from sleep (between midnight and 3 A.M) is
the most discriminating symptom (two-thirds of DU patients)
 Peptic Ulcer Disease
• Pain pattern in GU patients
discomfort may actually be precipitated by food
nausea and weight loss occur more commonly in GU patients
• Gastrointestinal bleeding is the most common complication
observed in PUD (15%)  tarry stools or coffee-ground emesis
• The second most common complication: perforation (6-7%)
 Treatment Approach
1. Eradicating the H. pylori infection
2. Reducing secretion of gastric acid with the use of H2-receptor antagonists
or PPIs
3. Providing agents that protect the gastric mucosa from damage, such as
misoprostol and sucralfate
4. If patients are unable to tolerate the above therapies, neutralizing gastric
acid with nonabsorbable antacids is an option.
 Drugs Used in Acid-Peptic Disease

1. Antacids 5. Misoprostol
2. H2-receptor antagonists 6. Colloidal bismuth
3. Proton pump inhibitors 7. Antibiotics
4. Sucralfate
 I. Antacids

• Weak bases that react with gastric acid to form water and a salt, thereby
diminishing gastric acidity.

• Because pepsin is inactive at a pH greater than 4, antacids also reduce

pepsin activity.
 I. Antacids

• The acid-neutralizing ability of an antacid also depends whether the stomach

is full or empty

food delays stomach emptying, allowing more time for the antacid to
react
 Commonly Used Antacids
Commonly used antacids are salts of aluminum and magnesium
• Aluminum hydroxide (Al[OH]3)
• Magnesium hydroxide [Mg(OH)2]
• Calcium carbonate [CaCO3] reacts with HCl to form CO2 and CaCl2.
 Has systemic effect  less popular
• Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient
metabolic alkalosis; therefore, this antacid is not recommended for long-term use.
 Therapeutic Uses of Antacids
• Aluminum- and magnesium-containing antacids are used for symptomatic
relief of peptic ulcer disease and GERD
• They may promote healing of duodenal ulcers, but the evidence for efficacy
in the treatment of acute gastric ulcers is less compelling; therefore, these
agents are used as LAST-LINE THERAPY.
• Calcium carbonate preparations are also used as calcium supplements for the
treatment of osteoporosis.
Adverse Effects of Antacids
• Aluminum hydroxide: constipation
• Magnesium hydroxide: diarrhea
• Sodium bicarbonate: systemic alkalosis;
liberates CO2  belching and flatulence.
• Calcium carbonate: excessive intake of drug
along with calcium foods  hypercalcemia.
 II. H2- Receptor Antagonists
• Chief clinical use: to inhibit gastric acid secretion
particularly effective against nocturnal acid secretion.
• By competitively blocking the binding of histamine to H2
receptors, these agents reduce the intracellular concentrations
of cyclic adenosine monophosphate and, thereby, secretion of
gastric acid.
 II. H2- Receptor Antagonists
• The four drugs used commonly are: cimetidine, ranitidine, famotidine,
and nizatidine
 potently inhibit (greater than 90 percent) basal, food-stimulated, and nocturnal
secretion of gastric acid after a single dose.
• Cimetidine
 the prototype histamine H2-receptor antagonist
 its utility however is limited by its adverse effect profile and drug interactions
 Mechanism of Action
• Act selectively on H2 receptors in the stomach, blood vessels, and other sites,
but they have no effect on H1 receptors.
• They are competitive antagonists of histamine and are FULLY
REVERSIBLE.
• These agents completely inhibit gastric acid secretion induced by histamine
or gastrin.
• However, they only partially inhibit gastric acid secretion induced by
acetylcholine or bethanechol.
 Therapeutic Uses
The use of these agents has decreased with the advent of the PPIs.
A. Peptic Ulcers
• All four agents are equally effective in promoting healing of duodenal
and gastric ulcers. However, recurrence is common after treatment
with H2 antagonists is stopped.
• Patients with NSAID-induced ulcers should be treated with PPIs,
because these agents heal and prevent future ulcers better than H2
antagonists.
 Therapeutic Uses
B. Acute Stress Ulcers
• These drugs are useful in managing acute stress ulcers associated with
major physical trauma in high-risk patients in intensive care units.

• They are usually injected intravenously.

 Therapeutic Uses
C. Gastroesophageal Reflux Disease
• appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux)
• however, about 50 percent of patients do not find benefit, and PPIs are now used
preferentially in the treatment of this disorder.
• because H2-receptor antagonists act by stopping acid secretion, they may not relieve
symptoms for at least 45 minutes
• antacids more efficiently, but temporarily, neutralize secreted acid already in the stomach
• tolerance to the effects of H2 antagonists can be seen within 2 weeks of therapy
 Adverse Effects
• Side effects occur only in a small number of patients and generally do not require
discontinuation of the drug.
• Most common side effects: headache, dizziness, diarrhea, and muscular pain
• Cimetidine can also have endocrine effects, because it acts as a nonsteroidal
antiandrogen.
 gynecomastia
 galactorrhea (continuous release/discharge of milk)
 reduced sperm count
 Adverse Effects

• Drugs such as ketoconazole, which depend on an acidic medium for gastric

absorption, may not be efficiently absorbed if taken with one of these
antagonists.
 III. Proton Pump Inhibitors
• Omeprazole and other proton pump inhibitors (esomeprazole, lansoprazole,
pantoprazole, and rabeprazole) are lipophilic weak bases that diffuse into the
parietal cell canaliculi, where they become protonated and concentrated more than
1000-fold.

• There they undergo conversion to compounds that IRREVERSIBLY

INACTIVATE the parietal cell H+/K+ ATPase, the transporter that is primarily
responsible for producing stomach acid.
 III. Proton Pump Inhibitors

• It takes about 18 hours for the enzyme to be resynthesized.

• At standard doses, all PPIs inhibit both basal and stimulated gastric acid
secretion by more than 90 percent.
 III. Proton Pump Inhibitors
• Oral formulations of these drugs are enteric coated to prevent acid
inactivation in the stomach.
• After absorption in the intestine, they are rapidly metabolized in the liver,
with half-lives of 1–2 h.
• However, their durations of action are approximately 24 h, and they may
require 3–4 d of treatment to achieve their full effectiveness.
 III. Proton Pump Inhibitors

• More effective than H2 antagonists for GERD and peptic ulcer and equally
effective in the treatment of nonulcer dyspepsia and the prevention of
stress-related mucosal bleeding.

• They are also useful in the treatment of Zollinger-Ellison syndrome.

 III. Proton Pump Inhibitors
• For maximum effect, PPIs should be taken 30 minutes before breakfast or the
largest meal of the day.
• If an H2-receptor antagonist is also needed, it should be taken well after the PPI for
best effect.
• The H2 antagonists will reduce the activity of the proton pump, and PPIs
require active pumps to be effective.
• In patients with GERD in whom once-daily PPI is partially effective, increasing to a
twice-daily regimen or keeping the PPI in the morning and adding an H2 antagonist
in the evening may improve symptom control.
 Adverse Effects of PPI
• Occur infrequently
• Include diarrhea, abdominal pain, and headache
• Chronic treatment with proton pump inhibitors may result in
hypergastrinemia.
• Proton pump inhibitors may decrease the oral bioavailability of vitamin
B12 and certain drugs that require acidity for their gastrointestinal absorption
(eg, digoxin, ketoconazole).
 IV. Sucralfate
• An aluminum sucrose sulfate, sucralfate is a small, poorly soluble molecule
that polymerizes in the acid environment of the stomach.
• The polymer binds to injured tissue and forms a protective coating over
ulcer beds.
• Sucralfate accelerates the healing of peptic ulcers and reduces the recurrence
rate.
 IV. Sucralfate

• Unfortunately, sucralfate must be taken 4

times daily.

• Sucralfate is too insoluble to have significant

systemic effects when taken by the oral route;
toxicity is very low.
 V. Misoprostol

• An analog of PGE1, misoprostol increases mucosal protection

and inhibits acid secretion.

 enhance mucous bicarbonate secretion

 stimulate mucosal blood flow

 decrease mucosal cell turnover

 V. Misoprostol

• It is effective in reducing the risk of ulcers in users

of nonsteroidal anti-inflammatory drugs (NSAIDs)
but is not widely used because of the need for multiple
daily dosing and poorly tolerated adverse effects.
 V. Misoprostol

• The most common toxicity noted with this drug is diarrhea (10–30%
incidence)

• Other major toxicities include uterine bleeding and contractions

 contraindicated in women who may be pregnant

 women of childbearing age must be made clearly aware of this potential drug toxicity
 VI. Colloidal Bismuth

• Bismuth has multiple actions

formation of a protective coating on ulcerated tissue
stimulation of mucosal protective mechanisms
direct antimicrobial effects
sequestration of enterotoxins
VI. Colloidal Bismuth

• Bismuth causes black stools,

constipation & blackening of
the tongue.
 VII. Antibiotics
• Chronic infection with H pylori is present in most patients with recurrent
non-NSAID-induced peptic ulcers.
• Eradication of this organism greatly reduces the rate of recurrence of ulcer
in these patients.
• The aim for initial eradication rates should be 85–90%.
• Dual therapy (eg. PPI plus amoxicillin) are not recommended in view of
studies demonstrating eradication rates of <80–85%.
 VII. Antibiotics

• Combination therapy for 14 days provides the greatest efficacy.

 A shorter course administration (7–10 days), although attractive, has not proved as
successful as the 14-day regimens.

• The agents used with the greatest frequency include amoxicillin,

metronidazole, tetracycline, clarithromycin, and bismuth compounds.
Drugs Used to Treat Peptic Ulcer Disease
Drugs that Promote Upper GI
Motility
 Drugs that Promote UGI Motility

• Prokinetic drugs that stimulate upper gastrointestinal motility are helpful for
gastroparesis and for postsurgical gastric emptying delay.

• Their ability to increase lower esophageal sphincter pressures also makes them
useful for some patients with GERD.

• In the enteric nervous system, dopamine serves as an inhibitory function by

inhibiting cholinergic stimulation of smooth muscle contraction.
 D2 Dopamine Receptor Antagonists

• Metoclopramide & Domperidone

 promote gastrointestinal motility

• The D2 receptor-blocking action of these drugs in the area postrema is

also of value in preventing emesis after surgical anesthesia and emesis
induced by cancer chemotherapeutic drugs.
 Drugs that Promote UGI Motility

• When used chronically, METOCLOPRAMIDE can cause symptoms of

parkinsonism, other extrapyramidal effects, and hyperprolactinemia.

• Because it does not cross the blood-brain barrier, DOMPERIDONE is less

likely to cause CNS toxicity.
 Laxatives
Drugs to Treat Constipation
 Laxatives
Laxatives increase the probability of a bowel movement by several mechanisms:
• An irritant or stimulant action on the bowel wall
• A bulk-forming action on the stool that evokes reflex contraction of the
bowel
• A softening action on hard or impacted stool
• A lubricating action that eases passage of stool through the rectum.
 Laxatives

• They all have a risk of being habit-forming.

• Laxatives also increase the potential of loss of pharmacologic effect of
poorly absorbed, delayed-acting, and extended-release oral preparations by
accelerating their transit through the intestines.
 A. Irritants & Stimulants

1. Senna
• PO: evacuation of the bowels within 8 to 10 hours.

• also causes water and electrolyte secretion into the bowel

• in combination products with a docusate-containing stool

softener, it is useful in treating opioid-induced constipation.
 A. Irritants & Stimulants

2. Bisacodyl
• available as suppositories and enteric-coated tablets

• a potent stimulant of the colon; acts directly on nerve

fibers in the mucosa of the colon

• adverse effects: include abdominal cramps and the

potential for atonic colon with prolonged use.
 A. Irritants & Stimulants

2. Bisacodyl
• Antacids should not be taken at the same time as the
enteric-coated tablets. The antacid would cause the
enteric coating to dissolve prematurely in the stomach,
resulting in stomach irritation and pain. The same adverse
effects could be expected with milk, H2-receptor
antagonists, and PPIs.
 A. Irritants & Stimulants

3. Castor Oil
• Broken down in the small intestine to ricinoleic acid, which is
very irritating to the gut, and promptly increases peristalsis.

• It should be avoided by pregnant patients, because it may

stimulate uterine contractions.
 B. Bulk Laxatives
• The bulk laxatives include hydrophilic colloids (from indigestible parts of
fruits and vegetables).
• They form gels in the large intestine, causing water retention and
intestinal distension, thereby increasing peristaltic activity.
• Similar actions are produced by methylcellulose, psyllium seeds, and bran.
• They should be used cautiously in patients who are bed-bound, due to the
potential for intestinal obstruction.
 C. Saline and Osmotic Laxatives

Saline cathartics

• Examples: magnesium citrate, magnesium sulfate, sodium phosphate, and

magnesium hydroxide

• Nonabsorbable salts (anions and cations) that hold water in the intestine by
osmosis and distend the bowel, increasing intestinal activity and producing
defecation in a few hours.
 C. Saline and Osmotic Laxatives
Lactulose
• a semisynthetic disaccharide sugar that also acts as an osmotic laxative
• cannot be hydrolyzed by intestinal enzymes
• oral doses are degraded in the colon by colonic bacteria into lactic, formic,
and acetic acids  this increases osmotic pressure, thereby accumulating
fluid, distending the colon, creating a soft stool, and causing defecation
 D. Stool Softeners
• A.k.a emollient laxatives or surfactants
• Surface-active agents that become emulsified with the stool produce softer feces
and ease passage.
• These include docusate sodium, docusate calcium, and docusate potassium.
• They may take days to become effective.
• They should not be taken together with mineral oil because of the potential for
absorption of the mineral oil.
 E. Lubricant Laxatives

• Mineral oil and glycerin suppositories are considered to be lubricants.

• They facilitate the passage of hard stools.
• Mineral oil should be taken orally in an upright position to avoid its
aspiration and potential for lipid or lipoid pneumonia.
Questions
 Question 1
A 55-year-old woman with type 1 diabetes of
40 yrs duration complains of severe bloating and
abdominal distress, especially after meals.
Evaluation is consistent with diabetic A. Alosetron
gastroparesis. Which of the following is a B. Cimetidine
prokinetic drug that could be used in this C. Loperamide
D. Metoclopramide
situation?
E. Sucralfate
 Answer: D

• Of the drugs listed, only

metoclopramide is considered a
prokinetic agent (ie, one that increases
propulsive motility in the gut)
 Question 2
A patient who is taking verapamil for
hypertension and angina has become
constipated. Which of the following A. Aluminum hydroxide
drugs is an osmotic laxative that could B. Diphenoxylate
be used to treat the patient’s C. Magnesium
constipation? hydroxide
D. Metoclopramide
E. Ranitidine
 Answer: C

• A laxative that mildly stimulates the gut would be most suitable in

a patient taking a smooth muscle relaxant drug such as verapamil.

• By holding water in the intestine, magnesium hydroxide

provides additional bulk and stimulates increased contractions.
 Question 3

Which drug accumulates in parietal cell A. Cimetidine

canaliculi and undergoes conversion to a B. Diphenoxylate
C. Esomeprazole
derivative that irreversibly inhibits
D. Metoclopramide
H+/K+ ATPase? E. Sulfasalazine
 Answer: C

• Esomeprazole, the (S) isomer of omeprazole, is a prodrug converting

spontaneously in the parietal cell canaliculus to a sulfonamide that
irreversibly inactivates the proton pump.
 Question 4

A 45-year-old woman with a duodenal ulcer was

treated with a combination of drugs intended to heal
A. Cefazolin
the mucosal damage and to eradicate Helicobacter
B. Ciprofloxacin
pylori. Which of the following antibacterial drugs is
C. Clarithromycin
used commonly to eradicate intestinal D. Clindamycin
Helicobacter pylori? E. Vancomycin
 Answer
• The macrolide antibiotic clarithromycin is commonly used in
• antibiotic regimens designed to treat duodenal ulcers caused
• by H pylori. The other antibiotics that are used include
• amoxicillin, tetracycline, and metronidazole. Bismuth also has
• an antibacterial action. The answer is C.
Antidiarrheal Agents
 A. Antimotility agents
• Two drugs that are widely used to control diarrhea are diphenoxylate and
loperamide.
• Both are analogs of meperidine and have opioid-like actions on the gut,
activating presynaptic opioid receptors in the enteric nervous system to
inhibit acetylcholine release and decrease peristalsis.
• At the usual doses, they lack analgesic effects.
 A. Antimotility agents
• Side effects include drowsiness, abdominal cramps, and dizziness.
• Because these drugs can contribute to toxic megacolon, they should not be used in
young children or in patients with severe colitis.

• Diphenoxylate is formulated with antimuscarinic alkaloids (eg, atropine) to reduce

the likelihood of abuse

• Loperamide is formulated alone

 B. Adsorbents
• Bismuth subsalicylate, methylcellulose, and aluminum hydroxide
• 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.
• They can interfere with the absorption of other drugs.
 B. Adsorbents
• Kaolin, a naturally occurring hydrated magnesium aluminum silicate, is
combined with pectin, an indigestible carbohydrate derived from apples in a
popular nonprescription preparation that absorbs bacterial toxins and
fluid, resulting in decreased stool liquidity.
• They can cause constipation and interfere with absorption of other
drugs.
 C. Agents that modify fluid and electrolyte
transport
• Bismuth subsalicylate
• used for traveler's diarrhea
• decreases fluid secretion in the bowel
Drugs Used of Irritable Bowel
Syndrome
 Irritable Bowel Syndrome (IBS)
• A functional bowel disorder characterized by abdominal pain or discomfort
and altered bowel habits in the absence of detectable structural
abnormalities
• Relapsing episodes of abdominal discomfort (pain, bloating, distention, or
cramps) plus diarrhea or constipation (or both)
• Women are diagnosed with IBS two to three times as often as men and
make up 80% of the population with severe IBS.
 Irritable Bowel Syndrome (IBS)
• Diagnostic Criteria:
Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months
associated with two or more of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool

• The pharmacologic strategy is tailored to patients’ symptoms and includes

antidiarrheal agents and laxatives, and for the treatment of abdominal pain, low
doses of tricyclic antidepressants.
 Drugs Used of Irritable Bowel Syndrome
Alosetron
• A potent 5-HT3 (serotonin) antagonist, is approved for treatment of
women with severe IBS with diarrhea.
• Can cause constipation, including rare complications of severe constipation
that have required hospitalization or surgery, and rare cases of ischemic
colitis.
 For this reason, its use is restricted.
 Drugs Used of Irritable Bowel Syndrome
Lubiprostone
• A laxative that activates the type 2 chloride channels in the small intestine
• Approved for treatment of women with IBS with predominant constipation
 Drugs with Antiemetic Actions
A variety of drugs are valuable in the prevention and treatment
of vomiting, especially cancer chemotherapy-induced vomiting.
 Phenothiazines
• Effective antiemetic agents
• Eg. prochlorperazine
• Acts by blocking dopamine receptors
• It is effective against low or moderately emetogenic chemotherapeutic agents
(for example, fluorouracil and doxorubicin).
• Although increasing the dose improves antiemetic activity, side effects, including
hypotension and restlessness, are dose limiting.
• Other adverse reactions include extrapyramidal symptoms and sedation.
 5-HT3 Receptor blockers
• Advantage: long duration of action.
• Ondansetron, granisetron, palonosetron and dolasetron
• Selectively block 5-HT3 receptors in the periphery (visceral vagal afferent
fibers) and in the brain (chemoreceptor trigger zone)
• These drugs can be administered as a single dose prior to chemotherapy
(intravenously or orally) and are efficacious against all grades of
emetogenic therapy.
 5-HT3 Receptor blockers
• These agents are extensively metabolized by the liver  doses of these
agents should be adjusted in patients with hepatic insufficiency.
• Headache is a common side effect.
• Electrocardiographic changes, such as prolongation of the QT interval,
can occur with dolasetron; therefore, patients who may be at risk should
receive this medication with caution.
• These drugs are costly.
 Substituted Benzamides
Metoclopramide
• Highly effective at high doses against the highly emetogenic cisplatin,
preventing emesis in 30 to 40 percent of patients and reducing emesis in the
majority.
• Antidopaminergic side effects, including sedation, diarrhea, and
extrapyramidal symptoms, limit its high-dose use.
 Butyrophenones
Droperidol and Haloperidol
• Act by blocking dopamine receptors
• Moderately effective antiemetics
• Droperidol may prolong the QT interval, and current practice reserves it
for patients whose response to other agents is inadequate.
• High-dose haloperidol was found to be nearly as effective as high-dose
metoclopramide in preventing cisplatin-induced emesis.
 Benzodiazepines
• The antiemetic potency of lorazepam and alprazolam is low.
• Their beneficial effects may be due to their sedative, anxiolytic, and amnesic
properties.
• These same properties make benzodiazepines useful in treating anticipatory
vomiting.
 Corticosteroids
Dexamethasone and Methylprednisolone
• Used alone, are effective against mildly to moderately emetogenic
chemotherapy
• Most frequently, however, they are used in combination with other agents.
• Their antiemetic mechanism is not known, but it may involve blockade of
prostaglandins.
• These drugs can cause insomnia as well as hyperglycemia in patients with
diabetes mellitus.
 Cannabinoids
• Marijuana derivatives, including dronabinol and nabilone, are effective
against moderately emetogenic chemotherapy.
• However, they are seldom first-line antiemetics because of their serious side
effects, including dysphoria, hallucinations, sedation, vertigo, and
disorientation.
• The antiemetic action of cannabinoids may not involve the brain.
Substance P/neurokinin-1 receptor blocker
Aprepitant
• Belongs to a new family of antiemetic agents.
• It targets the neurokinin receptor in the brain and blocks the actions of
the natural substance.
Substance P/neurokinin-1 receptor blocker
Aprepitant
• It undergoes extensive metabolism, primarily by CYP3A4. Thus, as would be
expected, it can affect the metabolism of other drugs that are metabolized by
this enzyme.
• Can also induce this enzyme and, thus, affect responses to other agents
 For example, concomitant use with warfarin can shorten the half-life of the
anticoagulant.
• Constipation and fatigue appear to be the major side effects.
 Combination Regimens
• Antiemetic drugs are often combined to increase antiemetic activity or decrease
toxicity.
• Corticosteroids, most commonly dexamethasone, increase antiemetic activity
when given with high-dose metoclopramide, a 5-HT3 antagonist,
phenothiazine, butyrophenone, a cannabinoid, or a benzodiazepine.
• Antihistamines, such as diphenhydramine, are often administered in
combination with high-dose metoclopramide to reduce extrapyramidal reactions
or with corticosteroids to counter metoclopramide-induced diarrhea.
Potencies
of
Antiemetic
Drugs
 Effectiveness of
antiemetic activity of
some drug combinations
against emetic episodes
in the first 24 hours after
cisplatin chemotherapy.
Drugs Used to Treat Chemotherapy-Induced
Nausea and Vomiting
Drugs Used in Inflammatory Bowel
Disease
 Inflammatory Bowel Disease (IBD)
• An immune-mediated chronic intestinal condition
• Two Major Types:
 Ulcerative colitis (UC)
 Crohn's disease (CD)
• The peak age of onset of UC and CD is between 15 and 30 years.
• A second peak occurs between the ages of 60 and 80.
 Inflammatory Bowel Disease (IBD)

• IBD is currently considered an inappropriate response to the endogenous

microbial flora within the intestine, with or without some component of
autoimmunity.
 Ulcerative Colitis
• A mucosal disease that usually involves the rectum and extends proximally
to involve all or part of the colon.
• With mild inflammation, the mucosa is erythematous and has a fine granular
surface that looks like sandpaper.
• In more severe disease, the mucosa is hemorrhagic, edematous, and
ulcerated.
• The major symptoms of UC are diarrhea, rectal bleeding, tenesmus,
passage of mucus, and crampy abdominal pain.
 Chron’s Disease
• Can affect any part of the gastrointestinal tract from the mouth to the anus
• Unlike UC, which almost always involves the rectum, the rectum is often
spared in CD.
• Unlike UC, CD is a transmural process.
• In more active disease, stellate ulcerations fuse longitudinally and transversely
to demarcate islands of mucosa that frequently are histologically normal.
This "cobblestone" appearance is characteristic of CD.
 Chron’s Disease
Ileocolitis
• Because the most common site of inflammation is the terminal ileum, the usual
presentation of ileocolitis is a chronic history of recurrent episodes of right
lower quadrant pain and diarrhea.
• Pain is usually colicky; it precedes and is relieved by defecation.
Jejunoiletis
• A loss of digestive and absorptive surface  malabsorption and steatorrhea
 Chron’s Disease

• Gross bleeding
(hematochezia) is not as
common as in UC and
appears in about half of
patients with exclusively
colonic disease.
 Aminosalicylates
• Drugs containing 5-aminosalicylic acid (5-ASA) are used as topical therapy for
IBD.
• The precise mechanism of 5-ASA action is uncertain but may involve inhibiting the
synthesis of prostaglandins and inflammatory leukotrienes, and interfering with
the production of inflammatory cytokines.
• 5-ASA, known generically as mesalamine, is readily absorbed from the small
intestine whereas absorption from the colon is extremely low.
• Proprietary formulations of 5-ASA (Pentasa, Asacol, Lialda) deliver 5-ASA to
different segments of the small and large intestine.
 Aminosalicylates
• Balsalazide, olsalazine, and sulfasalazine
• Sulfasalazine (a combination of 5-ASA and sulfapyridine) has a higher
incidence of adverse effects that the other 5-ASA drugs, due to the
systemic absorption of the sulfapyridine moiety.
 nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow
suppression, malaise, and severe hypersensitivity reactions
• Other aminosalicylates, which do not contain sulfapyridine, are well tolerated.
 Other Agents
Other drugs used in the treatment of ulcerative colitis and Crohn’s disease include:
• Antibiotics
• Glucocorticoids
• Immunosuppressive antimetabolites (eg, azathioprine, 6-mercaptopurine, methotrexate)
• Anti-tumor necrosis factor [TNF] drugs (eg, infliximab)
• Natalizumab is a humanized monoclonal antibody that blocks integrins on circulating
leukocytes
 because of a possible association of natalizumab with multifocal leukoencephalopathy, it is carefully
restricted to patients with severe refractory Crohn’s disease.
Therapeutic pyramid approach to
inflammatory bowel disease. Treatment
choice is predicted on both the severity
of the illness and responsiveness to
therapy. Agents at the bottom of the
pyramid are less efficacious but carry a
lower risk of serious adverse effects.
TNF, tumor necrosis factor.
Pancreatic Enzyme Replacements
 Pancreatic Enzyme Replacements
• Steatorrhea, a condition of decreased fat absorption together with an increase in
stool fat excretion, results from inadequate pancreatic secretion of lipase.
• The abnormality of fat absorption can be significantly relieved by oral
administration of pancreatic lipase (pancrelipase or pancreatin)
 obtained from pigs
• Pancreatic lipase is inactivated at a pH lower than 4.0
 the enzyme should be taken as enteric-coated capsules unless the pH is raised with antacids
or drugs that reduce acid secretion.
Drugs that Inhibit the Formation of
Gallstones
Drugs that Inhibit the Formation of Gallstones

• The formation of cholesterol gallstones can be inhibited by the bile acid

derivative ursodiol, which decreases the cholesterol content of bile by
decreasing hepatic cholesterol secretion and other effects on hepatocyte
canalicular membranes.
• Toxicity due to the drug is uncommon.
Questions
Question 1
A 34-year-old woman has irritable A. 5-HT3 receptor antagonist
bowel syndrome with diarrhea B. 5-HT4 receptor agonist
that is not responsive to
conventional therapies. Despite the C. D2 receptor antagonist
small risk of severe constipation and D. NK1 receptor antagonist
ischemic colitis, the patient decides
to begin therapy with alosetron. E. Muscarinic receptor antagonist
Alosetron has which of the
following receptor actions?
 Answer: A

• Serotonin plays a major regulatory role in the enteric nervous system, and
the potent 5-HT3 receptor antagonist alosetron has shown efficacy in
treating women with IBS that is accompanied by diarrhea.
 Question 2
A. Diphenhydramine
Which drug is most likely to be
B. Diphenoxylate
useful in the treatment of
C. Mesalamine
inflammatory bowel disease? D. Ondansetron
E. Ursodiol
 Answer: C

• Mesalamine is a form of aminosalicylate that releases 5-

aminosalicyclic acid in the large intestine and thereby provides a
local anti-inflammatory effect that is useful in inflammatory bowel
disease.
Question 3 A. Aluminum hydroxide
B. Diphenoxylate
On your way to an examination, you
experience the vulnerable feeling that an C. Loperamide
attack of diarrhea is imminent. If you D. Magnesium hydroxide
stopped at a drugstore, which one of
the following antidiarrheal drugs E. Metoclopramide
could you buy without a prescription
even though it is related chemically to
the strong opioid analgesic meperidine?
 Answer: C
• Aluminum hydroxide is constipating but is not related chemically to
meperidine
• Magnesium hydroxide is a strong laxative.
• The 2 antidiarrheal drugs that are structurally related to opioids are
diphenoxylate and loperamide.
• Loperamide is available over-the-counter; diphenoxylate is mixed with
atropine alkaloids; and, the product (Lomotil, others) requires a prescription.
Question 4

A patient is receiving highly emetogenic

chemotherapy for metastatic carcinoma. A. Levodopa
To prevent chemotherapy-induced nausea B. Methotrexate
and vomiting, she is likely to be treated C. Misoprostol
D. Ondansetron
with which of the following?
E. Sucralfate
 Answer: D

• The 5-HT3 receptor antagonists are highly effective at

preventing chemotherapy-induced nausea and vomiting, which
can be a dose-limiting toxicity of anticancer drugs.