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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.
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
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
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
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)
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
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
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.
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
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
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
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)
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. 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
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
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
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)
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.
Pathophysiology is multifaceted
Marc Imhotep Cray, M.D. 99
Treatment of Irritable Bowel Syndrome
Less flatulence may occur with polycarbophil agents than
psyllium ones
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
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
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
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
of Helicobacter pylori
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
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.
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. 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. 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)
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. 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.
Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.
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. 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
Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.
CINV not only affects quality of life but can also lead to
rejection of potentially curative chemotherapy
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).