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Radiograph of abdomen with radiopaque contrast (barium enema). Widmaier, EP. Vander’s human physiology 13th Ed.

New York: McGraw-Hill, 2014.
Marc Imhotep Cray, M.D.
Core Concepts and Learning Objectives
1. List the 5 different groups of drugs used in peptic ulcer disease.
2. Describe the mechanism of action of omeprazole and related
drugs.
3. List 7 different drugs used in the prevention of chemotherapy-
or radiation-induced emesis and identify the receptors with
which they interact.
4. Describe the mechanism of action, clinical uses, and adverse
effects of metoclopramide.
5. Identify 2 drugs commonly used as antidiarrheal agents and 4
drugs with different mechanisms that are used as laxatives.
6. Identify drugs used in the management of inflammatory bowel
disease and irritable bowel syndrome.
Marc Imhotep Cray, M.D. 2
Core Concepts & Learning Objectives cont.
7. Describe the most common causes of constipation.
8. Explain the mechanisms of action, indications, and
contraindications for drugs used for the relief of constipation
9. Describe an appropriate pharmacologic plan of therapy to
palliate the symptom of constipation.
10. Explain the pathophysiology of nausea and vomiting.
11. Explain the mechanisms of action, indications, and
contraindications for antiemetics.
12. Describe an appropriate pharmacologic plan of therapy to
palliate the symptoms of nausea and vomiting.

Marc Imhotep Cray, M.D. 3
Topical Outline
Introduction
 Disorders of Gastrointestinal Tract_Classification chart
 Disorders of Liver, Gallbladder, and Exocrine Pancreas_Classification
chart
 Drugs Used in Gastrointestinal Disorders_Classification chart
 Summary of drugs used to treat peptic ulcer disease
 Summary of drugs used to treat CINV
 Summary of drugs used to treat diarrhea
 Summary of drugs used to treat constipation
 Select GIT-related Abbreviations
 GI Tract Pharmacology High-Yield Terms
Overview of Gastrointestinal (GI) tract Pharmacology
Function and Regulation of the GI System
Disorders of Colonic Motility: Diarrhea, Constipation
Marc Imhotep Cray, M.D. 4
Topical Outline cont.
Functional Disorder of the Large Intestine:
Irritable Bowel Syndrome (IBS)
 Inflammatory bowel disease (IBD):Crohn’s disease and
ulcerative colitis
Protozoal GI Infection
Peptic Ulcer Disease
Gastroesophageal Reflux Disease
Pancreatitis
Gallstones (Cholelithiasis)
Liver Physiology, Pathology and Pharmacology
Nausea and Vomiting (Chemotherapy and Radiation-induced)

Marc Imhotep Cray, M.D. 5
Introduction to GI Tract

Marc Imhotep Cray, M.D. 6
Introduction
 Gastrointestinal tract is basically a tube that runs
through center of body from mouth to anus
 This tube consists of following organs:
o Mouth
o Pharynx
o Esophagus
o Stomach
o Small intestine
o Large intestine
 Although organs are continuous w one another each has
important anatomical modifications that allow it to carry out
its specific functions
Marc Imhotep Cray, M.D. 7
Introduction
 Accessory digestive organs exist outside GI tract
however, each of these organs empties secretions into
tract that contribute to process of digestion
 Accessory digestive organs include:
o Salivary glands
o Liver
o Gallbladder
o Pancreas

Marc Imhotep Cray, M.D. 8
Structure of GI Tract

Marc Imhotep Cray, M.D. Fox SI. Human Physiology, 12th ed. New York, NY: McGraw-Hill, 2011. 9
Four major processes GI tract carries out:

Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body Function, 14th Ed.
New York, NY: McGraw-Hill Education, 2016.

Marc Imhotep Cray, M.D. 10
Introduction cont.
 In addition to its main function of digestion and absorption of
food, GI tract is one of major endocrine systems (largest)

 Also, GI tract has its own integrative neuronal network,
enteric nervous system (ENS) which contains almost same
number of neurons as spinal cord
 ENS is site of many common pathologies, from simple dyspepsia to
complex autoimmune conditions such as Crohn’s disease
 medicines for treating GI disorders comprise some 8% of all
prescriptions

blood vessels and glands (exocrine, endocrine and paracrine)
of GI tract are under both neuronal and hormonal control
Marc Imhotep Cray, M.D. 11
Introduction
 This presentation will focus on medications used to treat
common medical conditions involving GI tract, including
1) Peptic ulcers
2) Gastroesophageal reflux disease (GERD),
3) Chemotherapy-induced emesis,
4) Diarrhea
5) Constipation
6) Irritable Bowel Syndrome
7) Inflammatory Bowel Disease and
8) Accessory digestive organ (liver, pancreas and gallbladder) disorders
 In each case mechanisms of action & therapeutic effects of
drugs discussed will be considered against their potential
adverse effects (AEs) & drug-drug and drug-pt. interactions
Marc Imhotep Cray, M.D. 12
Introduction
Several drugs described in other modules also find
application in treatment of GI disorders
 For example, the meperidine (opiate) derivative
diphenoxylate decreases peristaltic activity of gut is
useful in treatment of severe diarrhea

Other drugs are used almost exclusively to treat GI tract
disorders
 For example, H2- receptor antagonists (cimetidine) &
proton pump inhibitors [PPIs] (omeprazole) are used to heal
peptic ulcers
Marc Imhotep Cray, M.D. 13
Marc Imhotep Cray, M.D. 14
Baron SJ, Lee CI. Lange Pathology Flash Cards, 2nd Ed. New York: McGraw-Hill, 2009.
Baron SJ, Lee CI. Lange Pathology Flash Cards, 2nd Ed. New York:
McGraw-Hill, 2009. 15
Marc Imhotep Cray, M.D.
Pharmacologically treatable GI disorders
 Pharmacologically treatable GI disorders include:
 Peptic ulcer disease (PUD)
 Gastroesophageal reflux disease (GERD)
 Gastroparesis (delayed gastric emptying)
 Nausea and Vomiting
 Constipation
 Diarrhea
 Irritable bowel syndrome (IBS)
 Inflammatory bowel disease (IBD):Crohn’s disease and
ulcerative colitis
Also: Viral hepatitis B & C and complications of liver
 Pancreatitis disease and portal HTN (e.g., ALD) encephalopathy,
 Cholelithiasis ascites, varices, hyperbilirubinemia & coagulopathy.
Marc Imhotep Cray, M.D. 16
Trevor AJ, Katzung BG, Kruidering-Hall M . Katzung & Trevor’s Pharmacology Examination & Board
Review, 11th Ed. New York: McGraw-Hill Education, 2015.

Marc Imhotep Cray, M.D. 17
Summary of drugs used to treat Peptic Ulcer Disease
H2 – HISTAMINE RECEPTOR BLOCKERS PROSTAGLANDINS ANTIMICROBIAL AGENTS
Cimetidine TAGAMET Misoprostol CYTOTEC Amoxicillin AMOXIL, TRIMOX
Famotidine PEPCID ANTIMUSCARINIC AGENTS Bismuth compounds PEPTO-
Nizatidine AXID Dicyclomine BENTYL BISMOL, KAOPECTATE
Ranitidine ZANTAC ANTACIDS Clarithromycin BIAXIN
PROTON PUMP INHIBITORS (PPIs) Aluminum hydroxide ALTERNAGEL Metronidazole FLAGYL
Dexlansoprazole DEXILANT Calcium carbonate TUMS Tetracycline SUMYCIN
Esomeprazole NEXIUM Magnesium hydroxide MILK OF
Lansoprazole PREVACID MAGNESIA
Omeprazole PRILOSEC Sodium bicarbonate NUMEROUS
Pantoprazole PROTONIX MUCOSAL PROTECTIVE AGENTS
Rabeprazole ACIPHEX Bismuth subsalicylate PEPTO-BISMOL
Sucralfate CARAFATE

Marc Imhotep Cray, M.D. 18
Summary of drugs used to treat chemotherapy-
induced nausea and vomiting (CINV)
PHENOTHIAZINES BENZODIAZEPINES
Prochlorperazine COMPAZINE Alprazolam XANAX
5-HT3 SEROTONIN RECEPTOR BLOCKERS Lorazepam ATIVAN
Dolasetron ANZEMET CORTICOSTEROIDS
Granisetron KYTRIL Dexamethasone DECADRON
Ondansetron ZOFRAN Methylprednisolone MEDROL
Palonosetron ALOXI SUBSTANCE P/NEUROKININ-1
SUBSTITUTED BENZAMIDES RECEPTOR BLOCKER
Metoclopramide REGLAN Aprepitant EMEND
BUTYROPHENONES
Droperidol
Haloperidol HALDOL
Marc Imhotep Cray, M.D. 19
Summary of drugs used to treat diarrhea
ANTIMOTILITY AGENTS
Diphenoxylate + atropine LOMOTIL
Loperamide IMODIUM A-D
ADSORBENTS
Aluminum hydroxide ALTERNAGEL
Methylcellulose CITRUCEL
AGENTS THAT MODIFY FLUID AND
ELECTROLYTE TRANSPORT
Bismuth subsalicylate PEPTO-BISMOL

Marc Imhotep Cray, M.D. 20
Summary of drugs used to treat constipation
IRRITANTS and STIMULANTS STOOL SOFTENERS
Bisacodyl CORRECTOL, DULCOLAX Docusate COLACE, DOCU-SOFT
Castor oil LUBRICANT LAXATIVES
Senna EX-LAX, SENOKOT Glycerin suppositories
BULK LAXATIVES Mineral oil
Methylcellulose CITRUCEL CHLORIDE CHANNEL ACTIVATORS
Psyllium METAMUCIL, FIBERALL Lubiprostone AMITIZA
SALINE and OSMOTIC LAXATIVES
Magnesium citrate CITROMA
Magnesium hydroxide MILK OF MAGNESIA
Polyethylene glycol MIRALAX
Lactulose CONSTULOSE, ENULOSE

Marc Imhotep Cray, M.D. 21
Select GI tract-related Abbreviations
5-ASA 5-Aminosalicylic acid GI Gastrointestinal
5-HT 5-Hydroxytryptamine (serotonin) H. pylori Helicobacter pylori
ACh Acetylcholine IBD Inflammatory bowel disease
AChE Acetylcholine Esterase M Muscarinic
CB Cannabinoid IBS Irritable bowel syndrome
CNS Central nervous system NK Neurokinin (substance P)
COX Cyclooxygenase NSAID Nonsteroidal
CTZ Chemoreceptor trigger zone antiinflammatory drug
CYP Cytochrome P450 PPIs Proton pump inhibitors
DA Dopamine PUD Peptic ulcer disease
GERD Gastroesophageal reflux disease TNF Tumor necrosis factor
ENS Enteric Nervous System

Marc Imhotep Cray, M.D. 22
GI Tract Pharmacology High-Yield Terms
 Acid-peptic disease A group of disorders involving erosion or
ulceration of mucosal lining of GIT; includes GERD, gastric and
duodenal ulcers, nonulcer dyspepsia, and stress-related
gastritis
 Antiemetic A drug that reduces nausea and vomiting
 Gastroesophageal reflux disease (GERD) Esophageal irritation
or inflammation due to reflux of stomach acid; also known as
heartburn
 Gastroparesis Paralysis of muscles of stomach and possibly
other parts of GIT due to damage to gastrointestinal nerves or
muscle; common in advanced diabetes and advanced
Parkinson’s disease
Marc Imhotep Cray, M.D. 23
High-Yield Terms cont.
Inflammatory bowel disease (IBD) Inflammatory disorder
involving irritation and ulceration of colon and rectum
(ulcerative colitis) or colon plus more proximal parts of the GI
tract (Crohn’s disease), alone with systemic manifestations
Irritable bowel syndrome (IBS) Disease of unknown origin
characterized by episodes of abdominal discomfort and
abnormal bowel function (diarrhea, constipation, or both)
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

Marc Imhotep Cray, M.D. 24
Overview of Gastrointestinal
(GI) tract Pharmacology

Marc Imhotep Cray, M.D. 25
Overview of GI tract Pharmacology
 Gastrointestinal (GI) tract [GUT] is an epithelium-lined
muscular tube that runs from mouth to anus

 Major functions of GI system are food digestion, nutrient
absorption, and delivery of nutrients to blood for distribution

 Other functions are excretion of waste and secretion of
hormones into blood for delivery to distal targets & same
system

 GI system has an important role in fluid & electrolyte balance
 normal route for water & salt intake and a potential source of fluid
and electrolyte loss
Marc Imhotep Cray, M.D. 26
Overview of GI Tract Pharm (2)
During digestion, a large volume of digestive secretions are
added to ingested, chewed, and swallowed food
 Nearly all of this combined mixture must be reabsorbed to avoid
major disturbances in fluid-electrolyte and acid-base balance

 Small intestine provides a large surface area for absorption of
nutrients and drugs
 Substances are moved through GI tract by peristalsis
 Abnormally fast or slow peristalsis can disrupt absorption of nutrients,
drugs, and water origin of most GI dysfunctions, including:
constipation, diarrhea, peptic ulcer disease, gastroesophageal reflux
disease (GERD), and emesis

Marc Imhotep Cray, M.D. 27
Overview of GI Tract Pharm (3)
Constipation
Laxatives are used for Tx constipation cause emptying of
colon and defecation by stimulating peristalsis or by adding
more bulk or water to feces

Diarrhea
Opioids (diphenoxylate and loperamide) are most effective
drugs for controlling diarrhea
 Diarrhea is also treated with antiinflammatory drugs such as NSAIDs
aspirin and indomethacin
 Bismuth compounds (OTC) are used for simple diarrhea

Marc Imhotep Cray, M.D. 28
Overview of GI Tract Pharm (4)
 Peptic ulcer disease (an acid-peptic disease) is caused by an
erosion of mucosal layer of stomach or proximal small
intestine (duodenum)
 Helicobacter pylori infection is most common cause
 GERD is a similar disorder (acid-peptic disease) that occurs
in esophagus and is treated with similar medications

 PUD is best treated by a combination of lifestyle changes and
drugs

Marc Imhotep Cray, M.D. 29
Overview of GI Tract Pharm (5)
Histamine H2-receptor antagonists are firstline drugs for peptic
ulcers
 These blockers reduce stomach acidity without (for the most part)
producing adverse effects cimetidine can be problematic
Proton pump inhibitors (PPIs) are effective at reducing gastric
acid secretion by irreversibly inhibiting H+/K+ ATPase, which
blocks final step in acid secretion an enzyme expressed by
stomach parietal cells
 PPIs are therapeutically effective but usually must be discontinued b/c
of an AE profile (increased incidence of respiratory & enteric infections

Marc Imhotep Cray, M.D. 30
Overview of GI Tract Pharm (6)
 Antacids directly neutralize stomach acid however,
duration of action is limited by stomach-emptying time
 Antacids neutralize stomach acid and blunt reflux disease
symptoms
 Firstline drugs for GERD
NB. “Although agents in this class have traditionally been referred to as
antacids, term antacid has much wider use and applies to each of
many classes of drugs that reduce acid secretion. The more
appropriate term for agents in class is buffer, as this describes their
mechanism and distinguishes them from other classes.”
Bardal SK, Waechter JE, Martin DS. Applied pharmacology. St. Louis, Missouri: Saunders, 2011.

Marc Imhotep Cray, M.D. 31
Overview of GI Tract Pharm (7)
Buffers (Antacids) cont.
 Systemic antacid Sodium bicarbonate (rarely used due to
AEs)
o It is readily absorbed into body
o AEs common, including metabolic alkalosis, hypernatremia, fluid
retention, & acid rebound, due to high gastric pH
 Nonsystemic antacids are poorly absorbed into body
o Magnesium hydroxide induces side effect of diarrhea, whereas
o aluminum hydroxide induces constipation thus, magnesium
hydroxide and aluminum hydroxide are combined to create an
antacid preparation with little effect on GI motility
o Calcium carbonate (Tums) has more AEs, including hypercalcemia
(e.g., milk alkali syndrome), acid rebound, and constipation

Marc Imhotep Cray, M.D. 32
Overview of GI Tract Pharm (8)
 Several drugs are available to treat nausea,
vomiting (N/V), and motion sickness
 These agents include
o Histamine-H1 (1st generation) antagonists,
o corticosteroids,
o phenothiazines(D2 receptor antagonist),
o benzodiazepines, and
o Serotonin(5-HT3) receptor antagonists

Marc Imhotep Cray, M.D. 33
Function and Regulation of
the Gastrointestinal System

Marc Imhotep Cray, M.D. 34
Functions of
Organs of
Digestive
System

Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body
Marc Imhotep Cray, M.D. Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016. 35
Regulation of gastrointestinal function
 GI (or digestive) tract contains 3 types of sensory receptors
sensitive to chemical or mechanical changes, include:
1. Chemoreceptors respond to chemical components within GI lumen
 For example, in duodenum, chemoreceptors are stimulated by excessive
amounts of hydrogen ion secreted by stomach results in a motor response
that contracts pyloric sphincter (Why?)
2. Osmoreceptors breakdown of nutrients during digestion increases
number of molecules and therefore osmolarity of material being
processed excessive osmolarity may suggest absorption is not
keeping pace with digestion can result in osmotic diarrhea
3. Mechanoreceptors respond to stretch or distension of GI tract wall

Marc Imhotep Cray, M.D. 36
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 37
Regulation of GI function cont.
 Receptor stimulation may lead to activation of any or all of
following regulatory mechanisms (3) within GI tract:

 Intrinsic nerve plexuses (Enteric Nervous System)
o independent of CNS intratract reflexes provide a mechanism for
self-regulation of tract and help to coordinate activity of organs
within it
 Extrinsic autonomic nerves (Autonomic Nervous System)
o effects of ANS divisions oppose each other: parasympathetic
stimulates most digestive activities, while sympathetic system
inhibits them
 Gastrointestinal hormones
o travel in circulatory system to other regions of tract, and influence
activity
Marc Imhotep Cray, M.D. of effector cells in that region 38
Enteric Nervous System (ENS)
 Nervous system (CNS & ANS) exerts a profound influence
on all digestive processes, including 
 motility,
 ion transport assoc. with secretion and absorption, and
 blood flow

 Some of this control emanates from connections betw.
digestive system and CNS--but just as important--digestive
system is endowed with its own, local nervous system,
referred to as enteric or intrinsic nervous system

Marc Imhotep Cray, M.D. 39
Enteric Nervous System (2)
 Principal components of ENS  2 networks or
plexuses of neurons both are embedded in wall of
digestive tract and extend from esophagus to anus
 Myenteric (Auerbach) plexus is located betw.
longitudinal and circular layers of muscle in tunica
muscularis controls and coordinates motility
Submucosal (Meissner) plexus located in submucosa
(hence the name), betw. muscularis mucosa and circular
muscle layer controls secretion and absorption, as
well as, local blood flow

Marc Imhotep Cray, M.D. 40
Functions of intrinsic system (3)
 Acts as mediator of information betw.
extrinsic nervous system & alimentary
tract
 Commands most functions of GI tube
especially motility and secretion
 Can execute neural function of gut
without extrinsic innervations

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed.
Marc Imhotep Cray, M.D. 41
Philadelphia, PA: Elsevier, 2014.
Enteric Nervous System (4)
Plexuses are interconnected & their ganglion cells
receive preganglionic parasympathetic fibers from
vagus nerve (cholinergic & excitatory)

Incoming sympathetic fibers are postganglionic
 In addition to innervating bld vessels, sm. mm and some
glandular cells directly some sympathetics terminate in
these plexuses  inhibit acetylcholine secretion

Marc Imhotep Cray, M.D. 42
Structure of gut in longitudinal section
Not shown are smaller blood vessels and lymphatics and neural terminations on muscles.

Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body
Marc Imhotep Cray, M.D. Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016. 43
Integration of Autonomic and Enteric
Nervous Systems
Enteric plexuses contain 3 types of neurons most multipolar
1. Motor neurons control GI motility, secretion, and absorption
 They act directly on smooth muscle, secretory cells (parietal, chief,
mucous, pancreatic exocrine cells), and GI endocrine cells
2. Sensory neurons receive information from sensory receptors
in mucosa and muscle
 respond to mechanical, thermal, osmotic, and chemical stimuli
 Chemoreceptors are sensitive to pH, glucose, & amino acids
 Sensory receptors in muscle respond to stretch and tension
3. Interneurons integrate information from sensory neurons
and transmit it to enteric motor neurons

Marc Imhotep Cray, M.D. 44
Integration of ANS and ENS cont.
Enteric neurons secrete ACh and Norepinephrine (NE)
 Neurons that secrete ACh are
o excitatory and stimulate smooth muscle contraction,
o increase intestinal secretions,
o release enteric hormones, and
o relax (dilate) blood vessels

 NE, released from extrinsic sympathetic neurons, is
inhibitory and opposes biologic actions of Ach

 ENS also secretes 5-hydroxytryptamine (5-HT), purines,
nitric oxide and other pharmacologically active peptides
Marc Imhotep Cray, M.D. 45
Integration of
ANS & ENS
Illustrated

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 46
Gastrointestinal Motility
 GIT (digestive system) shows 2 basic forms of motility are:
 Segmentation contractions move back and forth so that
a previously constricted region relaxes and a previously
relaxed region contracts
o results in thorough mixing of contents w digestive enzymes and
other secretions (more important in sm. intestine)

 Peristalsis contractions muscular contraction (ring of
contractions) moves along length of tract
o causes propulsion and forces contents forward (more important
in esophagus and stomach)

Marc Imhotep Cray, M.D. 47
Gastrointestinal Motility cont.
 Mixing ensures ingested materials are exposed to
digestive enzymes and properly absorbed
 In absence of mixing food is not in contact w epithelial
cells that absorb nutrients
 Segmentation contractions are a common type of mixing
motility seen especially in small intestine segmental
rings of contraction break down and mix food
 Alternating contraction and relaxation of longitudinal
muscle in gut wall also provides effective mixing of its
contents and moves contents down the GIT

Marc Imhotep Cray, M.D. 48
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 49
Factors Affecting Gastric Emptying

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Chemoreceptors respond to various chemical components within GI lumen
 For example, in duodenum of small intestine, chemoreceptors are stimulated by
excessive amounts of hydrogen ion secreted by stomach

Marc Imhotep Cray, M.D. 50
Sequence of
Gastric Motility

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 51
Control of Peristalsis
 Food in intestinal lumen causes smooth muscle contraction
above bolus and relaxation below so that a peristaltic wave
moves food down intestine from mouth to anus

 ENS controls peristalsis and can work separately from CNS--but
proper digestion needs– ENS and CNS coordination

 Parasympathetic and sympathetic neurons connect CNS and
digestive tract allows
 sensory information to be sent to CNS,
 CNS regulation of GI function and
 relay of non-GI system signals
Marc Imhotep Cray, M.D. 52
Control of Peristalsis cont.
 Sympathetic stimulation inhibits GI secretion and motor
activity and causes GI sphincter and blood vessel contraction

 Parasympathetic stimulation increases GI secretion and
motor activity and causes GI sphincter and blood vessel relax
and dilation (respectively)

 Important peristaltic reflexes are
 gastrocolic, in which stomach distension causes colonic
exodus, and
 enterogastric, in which small intestine distension or
irritation reduces stomach secretion and motor activity
Marc Imhotep Cray, M.D. 53
Hormones of the Gastrointestinal Tract
(regulatory substances)
 Endocrine system regulates GI function by secreting hormones

 Hormones are chemical messengers secreted into blood that
modify physiology of target cells

 Digestive function is affected by hormones produced in many
endocrine glands but greatest control is exerted by
hormones produced within GI tract

 GI tract is largest endocrine organ in body endocrine cells
within it referred to collectively as enteric endocrine system
Marc Imhotep Cray, M.D. 54
Hormones of Gastrointestinal Tract cont.
 Three of best-studied enteric hormones are
1. Gastrin: secreted from stomach and plays an important
role in control of gastric acid secretion

2. Cholecystokinin (CCK): a small intestinal hormone that
stimulates secretion of pancreatic enzymes and bile

3. Secretin: a hormone secreted from small intestinal
epithelial cells that stimulates secretion of bicarbonate-rich
fluids from pancreas and liver

Marc Imhotep Cray, M.D. 55
GIT Hormones

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 56
Gastrointestinal Tract Hormones (regulatory
substances) Table

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Note: Even during fasting, contractions (the MMC= “migrating myoelectric
complex”) occur at 90-minute intervals and clear the stomach of residual
food. Motilin is the mediator of these contractions.

Marc Imhotep Cray, M.D. 57
Gastrointestinal secretory products

Marc Imhotep Cray, M.D. Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017. 58
Parietal Cell Function Regulation
 Stomach’s parietal cells secrete approximately 2 L of
acid a day as hydrochloric acid
 acid eradicates bacteria, aids in digestion by solubilizing
food, and maintains optimal pH (1.8- 3.2) for the function of
pepsin, a digestive enzyme

 H+,K+-ATPase (the proton pump) is expressed on
parietal cell apical membranes and uses energy from
ATP hydrolysis to pump hydrogen ions into lumen in
exchange for potassium ions

Marc Imhotep Cray, M.D. 59
Parietal Cell Function Regulation cont.
 Three regulatory molecules stimulate acid secretion-ACh,
histamine, gastrin
 One regulatory molecules inhibits acid secretion-somatostatin
------
 Ach increases acid secretion by stimulating muscarinic (M1) receptors
 Histamine, a paracrine hormone released from enterochromaffin like
(ECL) cells, stimulates acid secretion by activating H2 receptors
 Gastrin, a hormone released by G cells (endocrine cells in gastric
epithelium), increases acid release by activating gastric receptors
 Somatostatin-- also secreted by gastric endocrine cells (D cells)– along
with prostaglandins (PGE1,PGE2), opposes stimulatory actions of
gastrin

Marc Imhotep Cray, M.D. 60
Secretions of gastric acid (H+) by parietal cell mediated by neurocrine,
paracrine, and endocrine mechanisms.
Medical or surgical blockade of these mechanisms affords therapeutic options.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 61
Pancreatic Secretion
 Exocrine pancreas secretion is under neural and
endocrine control

 Pancreatic secretions--major mechanism for
neutralizing gastric acid in small intestine-- are
stimulated by food entering stomach and chyme
entering small intestine

 Vagus nerve innervates pancreas (and stomach) and
applies a low-level stimulus for secretion in
anticipation of a meal
Marc Imhotep Cray, M.D. 62
Pancreatic Secretion cont.
 Most important stimuli for pancreatic secretion come from 3
enteric nervous system hormones
1. CCK is synthesized and secreted by duodenal endocrine
cells in response to partly digested proteins and fats in
small intestine
 CCK is released into blood and binds to receptors on pancreatic
acinar cells, which induces digestive enzyme secretion
2. Secretin is secreted in response to acid in duodenum,
stimulates pancreatic secretion of water and bicarbonate
3. Gastrin, like CCK, is secreted by stomach and stimulates
acid secretion by parietal cells and digestive enzyme
secretion by pancreatic acinar cells
Marc Imhotep Cray, M.D. 63
Pancreatic Secretion
Illustrated

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 64
Defecation
 Defecation (passing of feces through rectum and anus)
occurs via relaxation of involuntary and voluntary internal
anal sphincter and heeding rectosphincteric reflex

 Defecation is prevented by external anal sphincter
contraction

 Rectum filling with fecal material causes urge to defecate
 When external anal sphincter relaxes, rectal smooth muscle
contracts to force feces out

 Presence of food in stomach increases colon motility
Marc Imhotep Cray, M.D. 65
Defecation cont.
 A rapid parasympathetic response (stimulated GI motility by
depolarizing smooth muscle cells) is initiated
 CCK and gastrin mediate a slower hormonal response

 Disorders of large intestine motility may be caused by
emotional factors via extrinsic ANS e.g.
 IBS, a disorder worsened by stress--causes constipation or
diarrhea
 Megacolon (Hirschsprung disease), absence of colon
enteric nervous system causes intestinal contents near
constriction to accumulate and severe constipation

Marc Imhotep Cray, M.D. 66
Raffa RB.
Marc Netter'sCray,
Imhotep Illustrated
M.D. Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 67
Raffa RB.
Marc Netter'sCray,
Imhotep Illustrated
M.D. Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 68
Protein Digestion
 Proteolytic enzymes are packaged in vesicles in an inactive
form and  thus protected against harsh pH conditions of GI
tract
 Pepsin is a stomach enzyme derived from pepsinogen that
is active at low pH
o Pepsin cleaves peptide bond betw. acidic (aspartic or glutamic
acid) and aromatic (phenylalanine, tyrosine) amino acids This
endonuclease catabolizes proteins into smaller peptides
 Trypsin is a pancreatic enzyme derived from trypsinogen
that is active at slightly basic pH
o Trypsin hydrolyzes peptide bonds adjacent to basic amino acids
lysine and arginine thus hydrolyzing proteins into peptides

Marc Imhotep Cray, M.D. 69
Protein Digestion cont.
 Other endopeptidases, such as chymotrypsin and
enterokinase, digest proteins into multiple amino acid
fragments

 Pancreatic carboxypeptidase is an exopeptidase that
hydrolyzes dipeptides at carboxyl end

 Small intestine aminopeptidase is an exopeptidase that
hydrolyzes dipeptides from amino end

 Finally, dipeptidase liberates free amino acids

Marc Imhotep Cray, M.D. 70
Protein Digestion Illustrated

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 71
Fat Digestion
 Fat digestion and absorption depend on bile
 Bile is secreted by liver and released into gut by action of
CCK on gallbladder
 Bile acts as an emulsifier to break up fat globules to aid
digestion
 Pancreatic lipase is a water-soluble enzyme, thus acts only
on fat globule surfaces
 hydrolyzes neutral fats to give free fatty acids and 2-
monoglycerides
 Detergent action of bile salts, esp. lecithin, is needed to
disperse fat into small globules for efficient lipase action
Marc Imhotep Cray, M.D. 72
Fat Digestion cont.
 Bile also forms micelles—aggregates of free fatty acids,
monoglycerides, and bile—which help transport water-
insoluble fatty acids
 Micelles take fat digestion products away from digestion
site to be absorbed by enterocytes these products thus,
do not inhibit lipases (negative feedback)

 Poor fat absorption causes excess fat in stools, or steatorrhea
 Stools are bulky, pale, and odiferous

Marc Imhotep Cray, M.D. 73
Fat Digestion
Illustrated

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 74
Disorders of Colonic Motility:
Diarrhea and Constipation

Marc Imhotep Cray, M.D. 75
Colonic Motility Disorder and Diarrhea
 Motility patterns in colonic lumen include
 peristalsis, which propels luminal contents toward
rectum, and
 those that extend contact of luminal contents with
absorptive epithelial cells
o Prolonging contact facilitates absorption of fluid from
feces
o Processes that promote propulsive patterns produce
diarrhea
 Diarrhea is defined as loose, watery stools that occur at
least 3 times per day

Marc Imhotep Cray, M.D. 76
Pathophysiology of Diarrhea
Diarrhea can be acute (<2 weeks duration) or chronic (>4 weeks)
 Acute diarrhea is usually due to an infectious cause
 Most common noninfectious causes adverse effects of medications
In simplest terms diarrhea is due to not enough absorption or
too much secretion
 Osmotic ( malabsorptive ) diarrhea is due to malabsorbed nutrients or
poorly absorbed electrolytes that retain water in GI lumen
o occurs when ability to digest or absorb a particular nutrient is
defective and can be due to disordered mixing (altered motility),
pancreatic insufficiency (altered digestion), or damage to
enterocytes or their surface transporters (altered absorption)
o this type of diarrhea stops when patient fasts

Marc Imhotep Cray, M.D. 77
Pathophysiology of Diarrhea cont.
 Secretory diarrhea results when secretagogues maintain elevated rates
of fluid transport out of epithelial cells into GI tract lumen
o this type of diarrhea does not stop when patient fasts

These physiologic distinctions--osmotic vs secretory--are useful
in both diagnosis and therapy of diarrheal disorders

In transport capacity, small intestine far exceeds colon (owing
to enormous surface area of brush border)thus, infectious,
toxic, or other causes of heightened secretion in small
intestine can overwhelm absorptive mechanisms in colon
resulting in diarrhea
Marc Imhotep Cray, M.D. 78
Causes and Treatment of Diarrhea
 Bacterial infections, viral infections, adverse food reactions,
parasites, and functional bowel disorders, medications can
lead to diarrhea
 b/c dehydration is caused by diarrhea, treatments include
rehydration with electrolytes (eg, broths, soup, potassium
supplements) or
 slowing motility with loperamide, bismuth subsalicylate, or
kaolin pectin suspension
 Most types of diarrhea are caused by viruses, so antibiotics
are usually ineffective
 Raspberry or blueberry leaves are sometimes taken w tea
to alleviate some symptoms
Marc Imhotep Cray, M.D. 79
Causes of Diarrhea

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 80
Antidiarrheal Drugs
 Antidiarrheal drugs aim to decrease fecal water content by
increasing solute absorption and decreasing intestinal
secretion and motility
 Increased transit time facilitates water reabsorption
 Tx w these medicines are reserved for pts w significant &
persistent symptoms of diarrhea

Main 3 agents used include
1. Opioids
2. Bismuth subsalicylate (Pepto Bismol)
3. Octreotide (Sandostatin)

Marc Imhotep Cray, M.D. 81
Antidiarrheal Drugs: Opioids
Opioids act directly on opioid μ-receptors to decrease transit
rate, stimulate segmental (nonpropulsive) contraction, and
inhibit longitudinal contraction
 Diphenoxylate (Lomotil)
o Diphenoxylate & its active metabolite, difenoxin
(Motofen), are used for Tx of diarrhea and not analgesia
o used as a combination product w atropine to reduce
potential for abuse
o AE At high doses, may produce CNS effects, including
nausea & vomiting, sedation, & constipation

Marc Imhotep Cray, M.D. 82
Antidiarrheal Drugs: Opioids
 Loperamide (Imodium)
o opioid agonist with no CNS activity, except at very high
doses, but w marked effects on intestine
o It binds to opioid receptors in GI tract
o PK Loperamide has a faster onset and longer duration of
action than diphenoxylate
o AE/Toxicity Loperamide overdose can result in severe
constipation, paralytic ileus, and CNS depression

 NB Loperamide & diphenoxylate contraindicated in children, GI
infections and GI obstruction
Marc Imhotep Cray, M.D. 83
Antidiarrheal Drugs: Bismuth subsalicylate
 Bismuth subsalicylate (Pepto Bismol)
 salicylate in this agent inhibits prostaglandin and chloride secretion
in intestine to reduce liquid content of stools
 It is effective for both treatment and prophylaxis of traveler’s
diarrhea and other forms of diarrhea
 Bismuth subsalicylate forms a protective coating in GI tract and has
direct antimicrobial activity
o It is used to treat H. pylori infection
 also used effectively to bind toxins produced by Vibrio cholerae and
Escherichia coli
 PK salicylate can be absorbed across intestine
 AE include tinnitus
 It may also produce black stools and staining of tongue

Marc Imhotep Cray, M.D. 84
Antidiarrheal Drugs: Octreotide
 Octreotide (Sandostatin)
 Octreotide is an analog of somatostatin effective for
treatment of diarrhea caused by short-gut syndrome and
dumping syndrome
 used in cases of severe diarrhea caused by excessive release
of GI tract hormones including gastrin & vasoactive
intestinal polypeptide (VIP)
 It is used treatment of neuroendocrine tumors of GI tract
 PK must be administered parenterally
 AE Octreotide causes mild GI dysfunction and formation of
gallstones due to alteration of fat absorption
Marc Imhotep Cray, M.D. 85
Other Antidiarrheal Drugs
 NSAIDs such as indomethacin and aspirin are thought
to relieve diarrhea by blocking COX-1 and inhibiting
prostaglandin synthesis
 most common AEs of aspirin are
o bleeding,
o respiratory depression,
o hypersensitivity reactions,
o hepatitis (particularly children), and
o salicylate toxicity

Marc Imhotep Cray, M.D. 86
Treatment of
Diarrhea

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 87
Causes of Constipation
 Constipation--one of most common GI problems in United
States--refers to passage of small amounts of hard and dry
stools
 Bowel movements occur fewer than 3 times a week

 Women (especially pregnant) and older adults (older than 65
years) report constipation most often

 Under normal conditions, colon absorbs water as food
passes through it and waste products (stool) form
 Stool becomes solid b/c most of water is absorbed

Marc Imhotep Cray, M.D. 88
Causes of Constipation cont.
 Hard and dry stools occur when colon absorbs too much
water or colon’s muscle contractions are slow

 Common symptoms are lethargy, feeling bloated, and painful
bowel movements
 Causes can be metabolic & endocrine; neurogenic (involving
CNS or PNS); medications; and idiopathic include
 lack of dietary fiber  aging
 inadequate hydration  laxative abuse
 lack of exercise  ignoring urges to have a BM
 IBS  stroke
 changes in life routines  colonic disease and
(pregnancy, travel)  intestinal disease
Marc Imhotep Cray, M.D. 89
Causes of
Constipation

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 90
Treatment of Constipation
 Constipation can be treated pharmacologically w laxatives
(along with appropriate lifestyle and dietary habits)
 Laxatives (stool softeners and cathartics) act primarily on
large intestine to promote an
 increase in fluid accumulated in bowel,
 decrease net absorption of fluid from bowel, or
 alter bowel motility
o These actions facilitate evacuation of fecal material

CAUTION Laxatives should not be used chronically as they may
induce “laxative dependence”

Marc Imhotep Cray, M.D. 91
Diagnosis &
Management
of Constipation

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 92
Classes and MOA of laxatives encapsulated
1. Bulk-forming laxatives (fiber supplements) are considered
safest but can interfere w absorption of some drugs
 They are taken w water & absorb water in intestine to make stool
softer
2. Osmotic laxatives (saline vs non-saline) draw water into colon
for easier passage of stool
3. Stimulant (irritant) laxatives cause rhythmic muscle
contractions in intestines
4. Stool softeners provide moisture to stool, prevent
dehydration used after childbirth and surgery
 Lubricants (mineral oil) add oil to stool allows stool to
move through intestine more easily
Marc Imhotep Cray, M.D. 93
Functional Disorder of the
Large Intestine:
Irritable Bowel Syndrome (IBS)

Marc Imhotep Cray, M.D. 94
Irritable Bowel Syndrome
 IBS-- a functional disorder that mainly affects bowel-- causes
cramping, bloating, gas, diarrhea, and constipation
 Other names for IBS are spastic colon, mucous colitis, spastic colitis,
and nervous stomach

 IBS is caused by disturbed interaction of intestines, brain,
and ANS that alters bowel motility (motor function) or
sensory function

 Added dietary fiber may relieve constipation and diarrhea
but can lead to worsened bloating, distension and flatulence

Marc Imhotep Cray, M.D. 95
IBS

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 96
Marc Imhotep Cray, M.D.
Irritable Bowel Syndrome cont.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 97
Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 98
IBS Capsule
 Recurrent abdominal pain associated with ≥ 2 of following:
 Related to defecation
 Change in stool frequency
 Change in form (consistency) of stool
 No structural abnormalities

 Most common in middle-aged women

 Chronic symptoms may be diarrhea-predominant,
constipation-predominant, or mixed

 Pathophysiology is multifaceted
Marc Imhotep Cray, M.D. 99
Treatment of Irritable Bowel Syndrome
 Less flatulence may occur with polycarbophil agents than
psyllium ones

 Peripheral narcotic opiate antagonists (trimebutine and
fedotozine), serotonin antagonists (tegaserod), and
muscarinic antagonists (zamifenacin) are being studied
 Trimebutine, with equal affinity for μ-, δ-, and κ-opioid
receptors, stimulates small intestine transit but inhibits
colonic motility
 Serotonin blockers inhibit intestinal motility
 Muscarinic blockers inhibit colonic motility and GI secretion
 CCK and calcium channel antagonists may also be useful
Marc Imhotep Cray, M.D. 100
Inflammatory bowel disease (IBD):
Crohn’s disease and
ulcerative colitis

Marc Imhotep Cray, M.D. 101
Crohn’s disease vs. Ulcerative Colitis
Location: (see next slide for full contrast)
Crohn disease
 Any portion of GI tract, usually terminal ileum and
colon
 Skip lesions, rectal sparing
Ulcerative colitis
 Colitis = colon inflammation
 Continuous colonic lesions, always with rectal
involvement

Marc Imhotep Cray, M.D. 102
Inflammatory bowel disease (IBD)

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.
Marc Imhotep Cray, M.D. 103
Treatment of inflammatory bowel disease
 Primary therapy for IBD (ulcerative colitis and Crohn’s disease)
utilizes steroids and 5-aminosalicyclate (5-ASA), also called
mesalamine, to control inflammatory process
 MOA 5-ASA inhibits leukotriene production and has
antiprostaglandin and antioxidant activity
o Sulfasalazine, balsalazide and olsalazine (prodrugs for
mesalamine) and mesalamine itself are used in mild
to moderate ulcerative colitis and for maintenance of
remission in UC
 Other immunomodulating agents are also used in IBD ,
including azathioprine, mercaptopurine, methotrexate, and
cyclosporine
Marc Imhotep Cray, M.D. 104
Tx of IBD cont.
 Antibodies and antibody fragments that bind to tumor necrosis
factor alpha (TNF-α) block inflammatory cascade and can be
used in IBD

 Infliximab and adalimumab are monoclonal antibodies that
bind to and inhibit TNF-α
 TNF-α inhibitors are general reserved for disease refractory to more
conventional therapy
 Natalizumab is another monoclonal antibody that is used in
Crohn’s disease
 MOA It reduces intestinal inflammation by binding α-4
integrin a molecule that mediates adhesion of leukocytes
to endothelial receptors
Marc Imhotep Cray, M.D. 105
Protozoal GI Infection: Giardiasis

Marc Imhotep Cray, M.D. 106
Protozoal GI Infection: Giardiasis
 Giardiasis is most frequent cause of nonbacterial diarrhea in
North America
 Human giardiasis may involve diarrhea within 1 week after
ingestion of cyst environmental survival form and
infective stage of organism

 Illness normally lasts for 1 to 2 weeks, but cases of chronic
infections have lasted months to years
 Chronic cases, both those with defined immune
deficiencies and those without, are difficult to treat

Marc Imhotep Cray, M.D. 107
Giardiasis cont.
Pathogenesis
 Disease mechanism unknown some investigators report
organism produces a toxin, but others not being able to
confirm existence of toxin

Treatment
 Metronidazole is normally quite effective in terminating
infections
 Antibiotics such as albendazole, metronidazole, and
furazolidone are often prescribed to treat giardiasis
 paromomycin may be considered for pregnant women

Marc Imhotep Cray, M.D. 108
Protozoal
GI Infection

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 109
Protozoal GI Infection

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 110
Giardiasis Capsule
Organism: Giardia Lamblia
Disease: Giardiasis—bloating, flatulence, foul-smelling, fatty
diarrhea often seen in campers/hikers
Transmission: cysts in water
Diagnosis: multinucleated trophozoites(A) or cysts (B) in stool,
antigen detection A B

Treatment:
Metronidazole

Note: Other GI parasites Entamoeba histolytica, Cryptosporidium

Marc Imhotep Cray, M.D. 111
Peptic Ulcer Disease
Also see GI Pharm Tutorial 2, Pharmacotherapy of Gastric
Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease

Marc Imhotep Cray, M.D. 112
Acid-peptic Disease Capsule
 Acid-peptic diseases (GERD, PUD, esophagitis, gastritis etc.) are
disorders in which gastric acid and pepsin are necessary, but
usually not sufficient, pathogenic factors
 acid and pepsin in stomach normally do not produce
damage or symptoms b/c of intrinsic defense mechanisms
o stomach is protected by a number of factors, collectively referred
to as “mucosal defense,”  stimulated by local generation of
prostaglandins and NO
o If defenses are disrupted a gastric or duodenal ulcer may form

 Treatment and prevention of these acid-related disorders are
accomplished by decreasing gastric acidity and enhancing
mucosal defense
Marc Imhotep Cray, M.D. 113
Acid-peptic Disease Capsule cont.
 Large majority of benign gastric and duodenal ulceration is
due to H. pylori infection (most of remainder due to NSAID
use)
 Key role of Helicobacter pylori in pathogenesis of acid-peptic
diseases has stimulated new approaches to prevention and therapy

 Colonization of stomach with H. pylori is seen in virtually all
patients w a duodenal ulcer and in 70–80% of those w gastric
ulcers
 H. pylori stimulate increased acid secretion all pts colonized w H.
pylori develop gastritis, but only about 20% have ulcers or other
lesions
NB. H. pylori infection is carcinogenic and is the
leading cause of gastric carcinoma.
Marc Imhotep Cray, M.D. 114
PUD Pharmacotherapy Capsule
 Triple therapy including two antibiotics and a proton
pump inhibitor (e.g., amoxicillin, clarithromycin,
omeprazole) will kill the Helicobacter pylori that
causes most ulcers
 A permanent cure can be produced in many patients
 Antibiotic therapy is inappropriate for salicylate-induced
and nonsteroidal anti-inflammatory drug (NSAID)-induced
ulcers
 Metronidazole can be used in patients who are allergic to
penicillins
Marc Imhotep Cray, M.D. 115
Helicobacter pylori Infection Overview
 Helicobacter pylori, a spiral bacterium found in gastric mucous
layer or adherent to epithelial lining of stomach causes more
than 90% of duodenal ulcers and up to 80% of gastric ulcers

 Approximately 66% of world’s population is infected with H
pylori

 It causes chronic persistent and atrophic gastritis in adults and
children

Marc Imhotep Cray, M.D. 116
H pylori Infection Overview (2)
 Before H pylori was discovered in 1982, spicy food, acid,
stress, and lifestyle were considered major causes of ulcers
 Most pts had long-term pharmacotherapy w histamine antagonists
(H2 blockers) and PPIs
o These drugs relieve ulcer-related symptoms and gastric mucosal
inflammation but do not eradicate infection
o When acid suppression is removed, majority of H pylori–induced
ulcers recur
o Chronic infection with H pylori weakens natural defenses of
stomach lining against acid
 Agents that eradicate H pylori (antimicrobials), neutralize
stomach acid (antacids), and reduce stomach acid output (H2
blockers, PPIs) are now used in combination regimens
Marc Imhotep Cray, M.D. 117
Etiology and Pathogenesis

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
of Helicobacter pylori

Marc Imhotep Cray, M.D. …Illustration continues do on next slide… 118
Etiology and Pathogenesis
of H pylori cont.

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 119
Treatment of Helicobacter pylori Infection
 Antibiotics can eliminate infection in most patients,
with resolution of mucosal inflammation and minimal
ulcer recurrence

 H pylori is difficult to eradicate from stomach b/c
organism can develop antibiotic resistance
 Antibiotics are coadministered w a PPI and/or bismuth-
containing compounds, which have anti–H pylori effects

Marc Imhotep Cray, M.D. 120
Treatment of H pylori Infection cont.
 Therapy for H pylori infection consists of 2 weeks of 1 or 2
antibiotics, such as amoxicillin, tetracycline (not for children
younger than 12 years) metronidazole, or clarithromycin,
plus ranitidine, bismuth citrate, bismuth subsalicylate, or a
PPI
 Acid suppression by an H2 antagonist or PPI in conjunction with
antibiotics alleviates ulcer related symptoms (eg, abdominal pain,
nausea), heals gastric mucosal inflammation, and enhances efficacy
of antibiotics against H pylori at gastric mucosal surface

 Common combinations are a PPI, amoxicillin, and
clarithromycin or a PPI, metronidazole, tetracycline, and
bismuth subsalicylate
Marc Imhotep Cray, M.D. 121
Diagnosis and
Management of
H pylori

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 122
Tests for Helicobacter pylori

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 123
Peptic Ulcer Treatment
 Antacids, PPIs, H2 blockers, muscarinic antagonists (M1 blockers), and
misoprostol (prostaglandin E2 derivative) are commonly used
MOA
 PPIs (eg, Omeprazole (Prilosec), lansoprazole (Prevacid), and
esomeprazole (Nexium) bind irreversibly to and inactivate H+,K+-ATPase
pump which blocks acid secretion until more pumps are synthesized

 Antacids neutralize 90% of gastric acid at a pH of 3.3

 Histamine stimulates acid secretion by activating H2 receptors so drugs
that block H2 receptors (eg, cimetidine, ranitidine) reduce acid levels
 Common AEs are allergic reactions, inhibit phase 1 oxidation (hepatic cytochrome
P-450 system) (esp. cimetidine) and impotence, increase prolactin galactorrhea
Marc Imhotep Cray, M.D. 124
Peptic Ulcer Treatment
 Misoprostol stimulates mucous secretion which protects GI
endothelial cells from high acid levels
 used for NSAID induced ulcers and for prevention in persons on NSAIDs

 cytoprotective sucralfate (sucrose-sulfate-aluminum hydroxide)
stimulates bicarbonate, mucus, and prostaglandin secretion
 should not be coadministered w H2 antagonists or antacids b/c acid is
required for sucralfate to work

 ACh activates M1 receptors to stimulate acid release M1
blockers (eg, hyoscyamine) block this action and reduce GI acid
levels
Marc Imhotep Cray, M.D. 125
PUD Tx: Medications Site of Action

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 126
Site of action (molecular targets) on parietal
cells of three classes of antisecretory drugs

Rosenfeld GC and Loose DS. BRS Pharmacology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2014 .
Marc Imhotep Cray, M.D. 127
Sites of action antacids 2

Whalen K. (Ed.) Lippincott Illustrated Reviews, Pharmacology 6th Ed. Philadelphia, PA: Wolters Kluwer Health-
Lippincott Williams & Wilkins, 2014.

Marc Imhotep Cray, M.D. 128
Gastroesophageal Reflux
Disease (GERD)
Also see GI Pharm Tutorial 2, Pharmacotherapy of Gastric
Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease

Marc Imhotep Cray, M.D. 129
Gastroesophageal Reflux Disease Overview
 In GERD, stomach acids move back into esophagus called
reflux
 Esophagus moves swallowed food into stomach via peristalsis
 Reflux occurs when these muscles fail to prevent acid from moving
backward
 Starch, fat, and protein in food are broken down by hydrochloric
acid and enzymes (pepsin)
 mucous lining of stomach protects it from acid and enzymes but
esophageal lining offers only weak resistance to these substances
 GERD symptoms are usually short lived and infrequent, but
GERD is chronic in approx. 20% of cases

Marc Imhotep Cray, M.D. 130
GERD Overview cont.
 Esophagitis occurs when acid causes irritation or
Inflammation extensive esophageal damage and injury lead
to erosive esophagitis

 GERD symptoms can occur with no signs of esophageal
inflammation or injury (nonerosive esophageal reflux
disease, or NERD), but patients have some GERD symptoms
(burning sensations behind breastbone)
 Nerves near endothelial lining are exposed to acid, and pain results

Marc Imhotep Cray, M.D. 131
Complications of Peptic Reflux (Esophagitis
and Stricture)

Raffa RB. Netter's Illustrated Pharmacology,
Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 132
Complications of Peptic
Reflux (Esophagitis and
Stricture) cont.

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 133
Gastroesophageal Reflux Disease Treatment
 Proton pump inhibitors reduce acid reflux by blocking
expulsion of hydrogen ions by proton pumps
 standard agent used has been omeprazole
 Newer oral PPIs include lansoprazole,
esomeprazole, and rabeprazole but they do not
cure condition
o Even when drugs relieve symptoms completely,
condition usually recurs within months after drugs are
discontinued
o Chronic cases require treatment for life
Marc Imhotep Cray, M.D. 134
GERD Treatment cont.
 Celecoxib, rofecoxib, and valdecoxib COX-2 inhibitors,
reduce inflammation and pain in a manner similar to aspirin
and ibuprofen w lower gastric irritation
 Valdecoxib and rofecoxib were removed from U.S. market due to an
increased risk of heart attack and stroke
 Unlike aspirin, however, these COX-2 drugs block activity of
COX-2 which alters activity of COX-1
 important b/c COX-1 is constitutive (unvarying gene
expression regardless of molecular conditions), whereas
COX-2 is inducible (variable and dependent on molecular
conditions such as inflammation or infection)
o It is hoped COX-2 blockers will cause fewer peptic
ulcers and bleeding compared w aspirin
Marc Imhotep Cray, M.D. 135
Symptoms and Medical Management
of Sliding Esophageal Hiatus Hernia

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 136
Principles of medical management

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 137
Pancreatitis

Marc Imhotep Cray, M.D. 138
Treatment of Pancreatitis
 Pancreatitis is acute or chronic inflammation of pancreas
which secretes digestive enzymes into small intestine (for
fat, protein, and carbohydrate digestion) and insulin and
glucagon into blood (for glucose regulation)

 Acute pancreatitis is sudden and brief and caused by
gallstones or excessive alcohol consumption
 Dyspnea and hypoxia are common
 Treatment of acute pancreatitis includes use of IV fluids,
pain meds, oxygen, antibiotics (eg, imipenem-cilastatin),
or surgery

Marc Imhotep Cray, M.D. 139
Acute Pancreatitis

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 140
Chronic (Relapsing) Pancreatitis
 Chronic pancreatitis may develop if pancreatic injury
continues caused by digestive enzymes attacking and
destroying pancreatic tissue
 Prolonged alcohol abuse is a common cause, but chronic
form may occur after only 1 acute attack, esp. if a pt. has
damaged pancreatic ducts, cystic fibrosis, hypercalcemia, or
hyperlipidemia
 Chronic pancreatitis therapy includes use of antiinflammatory
agents, a high-carbohydrate, low-fat diet, and protease
pancreatic enzyme supplements
 Can also result in diabetes mellitus and require insulin
therapy
Marc Imhotep Cray, M.D. 141
Chronic (Relapsing)
Pancreatitis

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 142
Gallstones (Cholelithiasis)

Marc Imhotep Cray, M.D. 143
Pathologic Features of Gallstones
Gallstones develop in gallbladder from crystals of cholesterol
or bilirubin

Stones can be too small to be seen with eye (biliary sludge) or
can be the size of golf balls There may be 1 or hundreds of
stones

Presence of gallstones is called cholelithiasis

Obstruction by gallstones of cystic duct (that leads from
gallbladder to common bile duct) causes pain (biliary colic),
infection, and inflammation (cholecystitis)
Marc Imhotep Cray, M.D. 144
Features of Gallstones cont.
 Gallstone disease affects 10% to 15% of US population but
only 1% to 3% report symptoms in a given year

 Women, particularly during pregnancy, are at increased risk
b/c estrogen stimulates liver to remove more cholesterol from
blood and divert it into bile

 Avoidance of fatty meals or nonsurgical approaches are used
only in special situations (when a serious medical condition
prevents surgery and for cholesterol stones)
 Stones usually recur after nonsurgical intervention
Marc Imhotep Cray, M.D. 145
Cholelithiasis

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 146
Gallbladder with stones:
Gross and Radiograph

Fox SI. Human Physiology 12th ed. New York, NY: McGraw-Hill, 2011.

Marc Imhotep Cray, M.D. 147
Gallstone Pathogenesis and Treatment
Using drugs synthesized from bile acid to dissolve gallstones
is known as oral dissolution therapy
 Ursodiol and chenodiol work best for small cholesterol
stones
o Months of treatment may be necessary before all stones
dissolve
 AEs Both drugs cause mild diarrhea, and
o chenodiol may increase blood cholesterol levels and increase
activity of transaminase, hepatic enzymes
Contact dissolution therapy is an experimental procedure
that involves injecting a drug directly into gallbladder to
dissolve stones
Marc Imhotep Cray, M.D. 148
Gallstone Pathogenesis and Treatment cont.
 Drug methyl-tert-butyl ether can dissolve some stones
in 1 to 3 days, but it must be used carefully b/c it is a
flammable and toxic anesthetic

 Extracorporeal shock wave lithotripsy (ESWL) is use of
shock waves to disintegrate stones into tiny pieces that can
pass through bile ducts without causing blockage
 Attacks of biliary colic (intense pain) are common after treatment,
and success rate of ESWL is unknown

Marc Imhotep Cray, M.D. 149
Pathogenesis of
Gallstones

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 150
Predisposing Factors

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 151
Liver Physiology and Pathology
See Cirrhosis of the Liver and Portal Hypertension_Tutorial 1 and
ICM_ Systems-based Pathophysiologic High Yield Cases, CASE 68

Marc Imhotep Cray, M.D. 152
Liver Anatomy
 Structural units of liver liver lobules
 Functional units of liver liver acinus
 How are these liver acini defined?
 A collection of hepatocytes that receive a blood supply from
same arteriole and are drained by same venule
 What is unique about the liver’s blood supply?
 It receives some oxygenated blood and some deoxygenated
blood
o Oxygenated blood coming from hepatic artery off of
celiac axis
o Deoxygenated component coming from portal circulation
Marc Imhotep Cray, M.D. 153
Schematic of microscopic appearance of liver
Illustration description:

(a) Hepatic lobules are structural-
functional units of liver
(b) A small section of liver showing
location of bile canaliculi and ducts
with respect to blood and liver cells
(hepatocytes)
Hepatic portal veins communicate with
hepatic sinusoids and bring absorbed
substances to liver from small intestines
Hepatocytes take up and process
nutrients and other factors from
hepatic sinusoids
Bile (green) is formed by uptake by
hepatocytes of bile salts and secretion
into bile canaliculi
Finally, central veins, located at
center of each lobule, drain blood from Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body Function, 14th Ed.
lobules into systemic venous circulation New York, NY: McGraw-Hill Education, 2016.

Marc Imhotep Cray, M.D. 154
Liver Function
 Liver creates, regulates, stores, and secretes substances used by
GI system bile being major digestive chemical synthesized
 During a meal, bile is secreted by liver cells and moves through hepatic
duct system into small intestine used to break down fat molecules
 Between meals, gallbladder stores bile
 Bile serves as a waste disposal system for toxins removed from blood
by liver
 Liver plays a major role in regulation of blood glucose

 Liver also synthesizes, dissolves, and stores amino acids,
protein, and fat, and it stores several important vitamins (B12
and A)
Marc Imhotep Cray, M.D. 155
Liver Function
 Liver disposes of cellular waste and decomposes toxic
substances such as alcohol, with disposal occurring via bile
 b/c liver clears toxins, hepatocytes are organized for optimal
contact with sinusoids (leading to and from blood vessels) and
bile ducts

 Liver is unique in that it can regenerate, but this capacity can be
exceeded
Marc Imhotep Cray, M.D.by extensive damage 156
Liver Function
 Primary Fx is digestive to
produce and secrete bile
 Other functions
o Carbohydrate metabolism,
o Cholesterol metabolism,
o Fat metabolism,
o Amino acid and protein
synthesis
o Storage of fat soluble
vitamins
o vitamin B12, iron and copper
o Immune functions
o Detoxification and
biotransformation
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 157
Bilirubin Production and Excretion
 Specific hepatic cells produce bilirubin (unconjugated or
indirect) a degradation product of hemoglobin
 Hepatocytes sequester bilirubin, conjugate it with
glucuronic acid, and excrete it into bile
o Intestinal bacteria convert conjugated (direct) bilirubin into
urobilinogen which is returned to liver and bile or excreted by
kidneys
 Bilirubin assay is used to determine liver (jaundice) or
gallbladder dysfunction
 Jaundice occurs, as a result of liver disease or bile duct
blockage, when red blood cells are broken down too fast for
liver to process
Marc Imhotep Cray, M.D. 158
Bilirubin Production and Excretion cont.
 Hemoglobin is degraded to bilirubin by reticuloendothelial
system(RES)
 Bilirubin is carried in the circulation bound to albumin
 In liver, bilirubin is conjugated with glucuronic acid via
enzyme UDP glucuronyl transferase
 A portion of conjugated bilirubin is excreted in urine and a
portion is secreted into bile
 In intestine, conjugated bilirubin is converted to
urobilinogen which is returned to liver via enterohepatic
circulation, and urobilin and stercobilin, which are excreted
in feces (gives stool its brown color)
Marc Imhotep Cray, M.D. 159
Bilirubin Production and Excretion

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

Marc Imhotep Cray, M.D. 160
Cirrhosis of the Liver
Also see: Cirrhosis of the Liver and Portal Hypertension_Tutorial 1

 In cirrhosis, widespread nodules in liver combined with
fibrosis distort normal liver architecture, which interferes with
blood flow through organ
 lead to inability of liver to perform biochemical functions
 Most common cause is alcoholic liver disease, others are
 chronic viral hepatitis B, C, and D
 chronic autoimmune hepatitis
 inherited metabolic diseases (hemochromatosis, Wilson disease)
 bile duct diseases
 chronic congestive heart failure
 parasitic infections (schistosomiasis) and
 long-term exposure to toxins or drugs
Marc Imhotep Cray, M.D. 161
Cirrhosis cont.
 Cirrhosis is irreversible, but treatment of underlying liver disease
may slow its progression

 Cessation of alcohol intake stops progress of alcoholic cirrhosis

 Stopping a hepatotoxic drug or removal of an environmental
toxin also halts disease progression
 Interferon is used to treat viral hepatitis B and C
 Prednisone and azathioprine used to treat autoimmune
hepatitis
 Drugs such as ursodiol may help in primary biliary cirrhosis

Marc Imhotep Cray, M.D. 162
Nausea and Vomiting
(Chemotherapy-induced

Marc Imhotep Cray, M.D. 163
Physiology of Emesis
 Emesis is expulsion of undigested food through mouth
 Nausea, state preceding vomiting, is sensation of needing to
vomit
 Emesis is caused by allergy, food, anticancer drugs (eg,
cisplatin), hepatitis, stress, and pregnancy

 Central neural vomiting regulation is located in medulla
 Chemoreceptor trigger zone (CTZ), in Area Postrema on floor
of IV ventricle, is quite sensitive to chemicals
 Blood-brain barrier (BBB) is poorly developed in CTZ
(accessible to emetic agents in circulation)

Marc Imhotep Cray, M.D. 164
Physiology of
Emesis Illustrated

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
Marc Imhotep Cray, M.D. 165
Physiology of Emesis cont.
 Vomiting center (VC) integrates emetic response and is
located in dorsolateral border of medullar reticular formation
(includes nucleus tractus solitarius, parvicellular reticular
formation, and visceral and somatic motor nuclei)
 VC gets excitatory inputs from nerve endings of
o vagal sensory fibers in GI tract,
o vestibular nuclei,
o higher centers in cortex (vomiting induced by disgust),
o CTZ, and
o intracranial pressure receptors

Marc Imhotep Cray, M.D. 166
Physiology of Emesis
Illustrated (2)

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 167
Induced Emesis
 Vomiting induced by emetic
syrup of ipecac is occasionally
recommended for pediatric
ingestions, being managed at
home, in consultation w poison
center
 It no longer has a role in
hospital management of
poisonings in U.S.

Marc Imhotep Cray, M.D. Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 168
Antiemetics
 There are several classes of antiemetic drugs
 H1 antagonists (eg, dimenhydrinate, clizines,
diphenhydramine, hydroxyzine) block H1 receptors in
midbrain to relieve histamine-induced emesis
 Most H1 blockers have additional anticholinergic action
 Adverse Effects include drowsiness and loss of coordination
o Newer histamine blockers (2nd generation agents) are
not useful for vomiting b/c they cannot penetrate
blood-brain barrier= no drowsiness and loss of
coordination

Marc Imhotep Cray, M.D. 169
Antiemetics cont.
 Dopamine antagonists (eg, metoclopramide, domperidone,
chlorpromazine, droperidol) are usually used as antipsychotic
drugs but can suppress emesis by blocking D2 receptors in
area postrema and CTZ
 Benzodiazepines (eg, diazepam, lorazepam) are useful for
anticipatory nausea and vomiting before cancer therapy
 They are also used for vestibular disorders (vertigo, dizziness,
nystagmus)
 Muscarinic receptor antagonists have also been used
(scopolamine is no longer available)
 relieve emesis by blocking M1 receptors in vestibular nuclei

Marc Imhotep Cray, M.D. 170
Receptors, Transmitters, and Drugs Involved in Mediating Vomiting

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D. 171
Chemotherapy-induced Comparison of emetic potential of anticancer drugs.

nausea and vomiting (CINV)
 Nausea and vomiting produced by
chemotherapeutic agents demands
especially effective management
 Nearly 70% to 80% of patients who undergo
chemotherapy experience nausea and/or
vomiting
 Several factors influence incidence and
severity of CINV, including specific
chemotherapeutic drug (Figure); the dose,
route, and schedule of administration; and
patient variables
Whalen K. (Ed.) Lippincott Illustrated Reviews,
Pharmacology 6th Ed. WKH-LWW 2014. 172
Marc Imhotep Cray, M.D.
CINV cont.
 Young patients and women are more susceptible CINV than
older patients and men

 10% to 40% of patients experience nausea and/or vomiting in
anticipation of chemotherapy (anticipatory vomiting)

 CINV not only affects quality of life but  can also lead to
rejection of potentially curative chemotherapy

 Uncontrolled vomiting can produce dehydration, profound
metabolic imbalances, and nutrient depletion

Marc Imhotep Cray, M.D. 173
CINV cont.
 5-HT3 receptor blockers: include Efficacy of antiemetic drugs.
ondansetron, granisetron, and
palonosetron
 MOA selectively block 5-HT3
receptors in periphery (visceral vagal
afferent fibers) and in brain (CTZ)
 This class of agents are DOC in
treating CINV largely b/c of longer
duration of action and superior
efficacy
Whalen K. (Ed.) Lippincott Illustrated Reviews,
Pharmacology 6th Ed. WKH-LWW 2014.

Marc Imhotep Cray, M.D. 174
CINV cont.
Effectiveness of antiemetic activity
 Corticosteroids: dexamethasone and of some drug combinations against
emetic episodes in first 24 hours
methylprednisolone, used alone, are after cisplatin chemotherapy.

effective against mildly to moderately
emetogenic chemotherapy
 Most frequently, they are used in
combination with other agents
 Antiemetic MOA is not known it may
involve blockade of prostaglandins
 Combination regimens: Antiemetic
drugs are often combined to increase
antiemetic activity or decrease toxicity Whalen K. (Ed.) Lippincott Illustrated Reviews,
Pharmacology 6th Ed. WKH-LWW 2014.
Marc Imhotep Cray, M.D. 175
CINV cont.
 Substance P/neurokinin-1 receptor blocker: aprepitant
targets neurokinin receptor in brain and blocks actions of
natural substance
 Aprepitant is indicated only for highly or moderately emetogenic
chemotherapy regimens
 Aprepitant usually administered orally with dexamethasone and
a 5-HT3 antagonist
 PK & drug-drug interactions Aprepitant undergoes
extensive phase I metabolism- by CYP3A4- and it may slow
metabolism of other drugs metabolized by this enzyme
warfarin and oral contraceptives

Marc Imhotep Cray, M.D. 176
Emesis & Antiemetic Capsule
 Antiemetics antagonize D2 and 5HT3 Receptors in
chemoreceptor trigger zone (CTZ) of brain to prevent vomiting
 CTZ chemoreceptors sense chemical stimuli, whereas actual act of
vomiting is controlled by medulla

Classes of Medications Used:
 Anticholinergic drugs (scopolamine) and
 H1-antagonists (meclizine [Antivert], dimenhydrinate
[Dramamine]) prevent motion sickness but do not prevent
stimulation of CTZ

Marc Imhotep Cray, M.D. 177
Emesis & Antiemetic Capsule cont.
 Several drugs are used to control chemotherapy-induced
nausea and vomiting:
 D2 dopamine receptor antagonists include
prochlorperazine (Compazine), metoclopramide (Reglan),
and droperidol (Inapsine)
o AEs droperidol is assoc. w prolonged QT and torsades de pointes
 Odansetron (Zofran) is a 5HT3 serotonin receptor
antagonist DOC for potent ChemoTx agent induced N/V
 Cannabinoids like dronabinol (Marinol) work by an
unknown mechanism and are not commonly used
 Aprepitant (Emend) blocks neurokinin receptors in CTZ

Marc Imhotep Cray, M.D. 178
Comprehension Q & A

Marc Imhotep Cray, M.D. 179
Question 1
A 68-year-old patient with cardiac failure is diagnosed with
ovarian cancer. She begins using cisplatin but becomes nauseous
and suffers from severe vomiting.
Which of the following medications would be most effective to
counteract the emesis in this patient without exacerbating her
cardiac problem?
A. Droperidol
B. Dolasetron
C. Prochlorperazine
D. Dronabinol
E. Palonosetron

Marc Imhotep Cray, M.D. 180
Answer 1
Correct answer = E. Palonosetron is a 5-HT3 antagonist that is
effective against drugs with high emetogenic activity, such as
cisplatin. Although dolasetron is also in this category, its
propensity to affect the heart makes it a poor choice for this
patient. Droperidol also affects the heart and now is generally a
second-line drug used in combination with opioids or
benzodiazepines. The antiemetic effect of prochlorperazine, a
phenothiazine, is most beneficial against anticancer drugs with
moderate to low emetogenic properties.

Marc Imhotep Cray, M.D. 181
Question 2
A 45-year-old woman complains of persistent heartburn and an
unpleasant, acid-like taste in her mouth. The clinician suspects that
she has gastroesophageal reflux disease and advises her to raise
the head of her bed 6 to 8 inches, not to eat for several hours
before retiring, and to eat smaller meals. Two weeks later, she
returns and says the symptoms have subsided slightly but still are a
concern. The clinician will likely prescribe which one of the
following drugs?
A. An antacid such as aluminum hydroxide
B. Dicyclomine
C. An antianxiety agent such as alprazolam
D. Esomeprazole
Marc Imhotep Cray, M.D. 182
Answer 2
Correct answer = D. It is appropriate to treat this patient with a
proton-pump inhibitor (PPI) to reduce acid production and
promote healing. An H2-receptor antagonist might also be
effective, but the PPIs are preferred. An antacid would decrease
gastric acid, but its effects are short lived compared to those of
the PPIs and H2-receptor inhibitors. Dicyclomine is an
antimuscarinic drug and would decrease acid production, but it is
not as effective as the PPIs or the H2-receptor inhibitors. An
antianxiety agent might have antiemetic action but would have
no effect on the acid production.

Marc Imhotep Cray, M.D. 183
Question 3
A couple celebrating their 40th wedding anniversary are given a
trip to Ethiopia to visit Bale Mountain National Park. Due to
past experiences while traveling, they ask their doctor to
prescribe an agent for diarrhea. Which of the following would
be effective?
A. Omeprazole
B. Loperamide
C. Famotidine
D. Lorazepam

Marc Imhotep Cray, M.D. 184
Answer 3
Correct answer = B. Loperamide is the only drug in this set that
has antidiarrheal activity. Omeprazole is a proton-pump
inhibitor, famotidine antagonizes the H2 receptor, and
lorazepam is a benzodiazepine that is a sedative and an
anxiolytic agent.

Marc Imhotep Cray, M.D. 185
Question 4
A 27-year-old woman who is 34 weeks pregnant is on bed rest
and visits her obstetrician. During the visit, she informs her
physician that she has been experiencing mild constipation.
Which of the following medications will most likely be
recommended to her?
A. Castor oil
B. Docusate
C. Mineral oil
D. Loperamide

Marc Imhotep Cray, M.D. 186
Answer 4
Correct answer = B. Although its effects are not immediate,
docusate may be used for mild constipation and is generally
considered safe in pregnancy. Castor oil should not be used in
pregnancy because of its ability to cause uterine contractions.
Mineral oil should not be used in bedridden patients due to the
possibility of aspiration. Loperamide is used for diarrhea, not
constipation.

Marc Imhotep Cray, M.D. 187
Question 5
Which of the following drugs has been known to cause
discoloration of the tongue?
A. Amoxicillin
B. Omeprazole
C. Bismuth compounds
D. Lubiprostone

Marc Imhotep Cray, M.D. 188
Answer 5
Correct answer = C. Bismuth compounds may cause a black
discoloration of the tongue. The other agents have not been
associated with this effect. Correct answer = D. Ethanol combined
with benzodiazepines, particularly at high doses, may produce
unconsciousness, respiratory depression, and even death. The
other drugs listed here have not shown a specific drug interaction
with benzodiazepines.

Marc Imhotep Cray, M.D. 189
Question 6
A patient is receiving treatment with lorazepam prior to
chemotherapy to help reduce her anticipatory nausea and
vomiting. Which of the following should generally be avoided in
this patient?
A. Docusate
B. Ondansetron
C. Polyethylene glycol
D. Ethanol

Marc Imhotep Cray, M.D. 190
Answer 6
Correct answer = D. Ethanol combined with benzodiazepines,
particularly at high doses, may produce unconsciousness,
respiratory depression, and even death. The other drugs listed
here have not shown a specific drug interaction with
benzodiazepines.

Marc Imhotep Cray, M.D. 191
Question 7
All of the following drugs are generally well tolerated for the
treatment of constipation except:
A. Castor oil
B. Methylcellulose
C. Polyethylene glycol
D. Docusate

Marc Imhotep Cray, M.D. 192
Answer 7
Correct answer = A. Castor oil can produce severe cramping,
which makes it difficult to tolerate for many, including the
elderly. The other three choices are generally well tolerated.

Marc Imhotep Cray, M.D. 193
Question 8
An elderly woman with a recent history of myocardial infarction
is seeking a medication to help treat her occasional heartburn.
She is currently taking several medications, including aspirin,
clopidogrel, simvastatin, metoprolol, and lisinopril. Which of the
following choices should be avoided in this patient?
A. Calcium citrate
B. Famotidine
C. Omeprazole
D. Ranitidine
E. Calcium carbonate
Marc Imhotep Cray, M.D. 194
Answer 8
Correct answer = C. Omeprazole may possibly decrease the
efficacy of clopidogrel because it inhibits the conversion of
clopidogrel to its active form.

Marc Imhotep Cray, M.D. 195
Question 9
Extrapyramidal symptoms (EPS) have been associated with
which of the following drugs?
A. Metoclopramide
B. Alprazolam
C. Aprepitant
D. Loperamide

Marc Imhotep Cray, M.D. 196
Answer 9
Correct answer = A. Only metoclopramide has been associated
with EPS. This is due to its ability to inhibit dopamine activity.

Marc Imhotep Cray, M.D. 197
Question 10
10. Which of the following medications for gastrointestinal
problems is contraindicated in pregnancy?
A. Calcium carbonate
B. Famotidine
C. Lansoprazole
D. Misoprostol

Marc Imhotep Cray, M.D. 198
Answer 10
Correct answer = D. Misoprostol is contraindicated in pregnancy
because it may stimulate uterine contractions. The other
medications may be used during pregnancy for the treatment of
heartburn (common in pregnancy) or peptic ulcer disease.

Marc Imhotep Cray, M.D. 199
THE END

See next slide for hypermedia to further study tools and resources.
Marc Imhotep Cray, M.D. 200
Further study tools and resources:
IVMS Online Medical Pharmacology Course: (5 interactive and looping components.)
Instructor: Marc Imhotep Cray, M.D. Course Website: Link

1. Integrated Scientific and Clinical Pharmacology: A MS1 & MS2 Course Syllabus and Digital Guidebook
(©2015-17).

2. Medical Pharmacology: Core Concepts and Learning Objectives

3. Medical Pharmacology Case Studies

4. Medical Pharmacology Unit e-Notes

5. Medical Pharmacology Glossary of Terms

 e-Learning resource center: IVMS Medical Pharmacology Cloud Folder

Marc Imhotep Cray, M.D. 201