Objectives for Lecture on Nausea, Vomiting, Diarrhea,
and Constipation
• By the end of this class students will be able to:
– Explain the physiology of nausea and vomiting
– Name the drugs used to prevent vomiting associated with motion
sickness, cancer chemotherapy/radiation and surgery/anesthesia,
explain their mechanisms of action, and explain why they are
useful in that particular situation
– Name the drugs used to terminate diarrhea, explain their
mechanisms of action, and explain why they are useful for that
purpose
– List the drugs or classes of drugs (with examples) used to terminate
constipation and/or evacuate the bowel, explain their mechanisms
of action, and explain why they are useful in that particular
situation
– Choose the most appropriate pharmacotherapies at the
appropriate times to prevent nausea and vomiting, terminate
diarrhea, terminate constipation, and prepare the bowel for
invasive procedures
– Name the drugs used to treat inflammatory bowel disease, explain
their mechanisms of action, and explain why they are useful in that
particular situation
Nausea and Vomiting
• Nausea
–
–
–
–
GI discomfort that often precedes vomiting
Reduced gastric tone
Diminished peristalsis
Increase tone of distal GI tract
• Hinders transit
• Promotes reflux of contents
• Vomiting
– A complicated reflex intended to protect the body against ingested toxins
Input to and Output from the Vomiting Center
Inputs to the Vomiting Center
• Chemoreceptor Trigger Zone (CTZ)
– Exposed to both CSF and blood; surveys these fluids for injurious
substances
– Receptors: 5-HT3 (serotonin), D2 (dopamine), NK1 (substance P)
• Vestibular System
– Triggers vomiting associated with motion sickness
– Receptors: Muscarinic (acetylcholine), H1 (histamine)
• Visceral Afferent Fibers from GI Tract
– Trigger vomiting associated with mucosal damage
– Receptors: 5-HT3 (serotonin), NK1 (substance P)
• Cerebral Cortex
– Triggers vomiting associated with sensory/emotional stimuli
Stimuli for Nausea and Vomiting That May Require
Treatment
•
•
•
•
Motion Sickness
Cancer Chemotherapy/Radiation
Postsurgery/Anesthesia
Pregnancy
Motion Sickness
(inc. Vertigo, Meniere’s Disease)
H1
M
• Muscarinic antagonist
– Scopolamine (patch)
• H1/Muscarinic
antagonists
– Meclizine
– Diphenhydramine
– Dimenhydrinate
• Use scopolamine patch
(most effective) or
antihistamine
Cancer Chemotherapy/Radiation-Induced Nausea and
Vomiting
NK1
5-HT3
• 5-HT3 antagonists
– Ondansetron
• NK1 antagonists
– Aprepitant
• Glucocorticoids
– Dexamethasone
• Use in combination
Risk Factors for Postoperative Nausea and Vomiting
• Patient-related
–
–
–
–
–
Female gender
Previous history of PONV or motion sickness
Non-smoker
Obese
Postoperative narcotics
• Surgery-related
– Inhaled anesthesia
– Type of surgery
– Lengthy surgery
Postoperative Nausea and Vomiting
H1
M
D2
NK1
5-HT3
• 5-HT3 antagonists
– Ondansetron
• NK1 antagonists
– Aprepitant
• Glucocorticoids
– Dexamethasone
• D2 antagonists
– Prochlorperazine
– Droperidol
– Metoclopramide (also muscarinic
agonist)
Algorithm for Treatment of
Postoperative Nausea and Vomiting
Normal Water Transit in the Gut
• 10 L/day
• Only 0.1 L excreted
• Difference in just 1% causes
diarrhea
• Most occurs in small intestine
Causes of Diarrhea
• Infection
• Food malabsorption (lactose intolerance)
• Inflammatory Disease
– Secretion of mediators that increase intestinal secretion, reduced absorptive
surface
• Disordered motility
• Endocrinopathies
– Hyperthyroidism, Addison’s Disease
– Stress
• Laxative abuse
• GI Endocrine tumors
• Drugs: caffeine (Starbuck’s diarrhea)
Therapy of Diarrhea
• Treat the underlying cause, if known
• Normalize hydration and electrolytes
• Use bulk-forming and hygroscopic agents to decrease fluidity of
stool
• Reduce motility to allow greater absorption of fluid
Hydration and Electrolytes
• Provide water, sodium, potassium, and glucose
– Take advantage of Na+-glucose cotransport, which tends to be preserved
– Commercially-available rehydrating solutions include Pedialyte, Ricelyte
– Home remedy: 1 tsp salt, 8 tsp sugar, 0.5 tsp baking soda, 0.25 tsp salt
substitute in 1 L clean water
– Gatorade inadequate - not enough sodium
Bulk-forming, Hygroscopic and Anti-secretory Agents
• Fiber products - Metamucil, Fibercon, Citrucel (also used to treat
constipation)
– Absorb water, increase bulk
• Cholestyramine - binds bile salts, some bacterial toxins
– Diarrhea caused by excessive bile salts or some bacteria
• Bismuth subsalicylate (PeptoBismol)
– Converted to bismuth oxychloride in stomach
– Antisecretory, anti-inflammatory, antimicrobial
Peripherally-acting Narcotic
• Slows GI motility, thus promoting fluid
absorption, by activating mu receptors
• As effective as morphine
• Traveler’s diarrhea, Diarrhea associated with
inflammatory bowel disease
• Opioid that does not accumulate in CNS
– Loperamide (Imodium and others) – Transported by
P-glycoprotein; thus excluded from CNS
Causes of Constipation
•
•
•
•
Low bulk (non-digestible food) intake
Low physical activity (hospitalization!)
Inadequate water intake
Slow colon transit time- allows maximal water reabsorption
– Normal mean transit time: 35 hr
• Inflammatory disease
– Secretion of mediators that inhibit intestinal secretion
• Narcotic use
Treatment of Constipation (Outpatients)
•
•
•
•
Increase physical activity
Maintain adequate hydration
Increase bulk in diet
Stimulate motility (when the above prove inadequate and
with inpatients)
Bulk Agents
• Dietary
– Wheat bran
– Fruits and vegetables - pectins, hemicelluloses
• Commercial
– Metamucil, Fibercon, Citrucel
Osmotic Agents
• Non-digestible sugars
– Mannitol
– Lactulose – also traps ammonia due to reduced colon
pH
– Sorbitol
• Polyethyleneglycol-electrolytes (Golytely) – used
for bowel preps
• Saline cathartics – osmotically-active, nonabsorbable cations or anions; used for bowel preps
– Magnesium sulfate, magnesium hydroxide (Milk of
Magnesia), magnesium citrate, sodium phosphate
(Fleet)
Stool Softeners and Stimulant Cathartics
• Stool Softeners (relieve straining)
– Docusate (Colace, Dulcolax Stool Softener)
• Stimulant Cathartics
– Bisacodyl (Dulcolax)
– Cascara sagrada
– Senna (Senecot)
Chronic Constipation
• Constipation that does not respond to bulk agents or stimulant
cathartics
• Several forms:
–
–
–
–
–
Chronic Idiopathic Constipation
Constipation from surgery followed by restricted activity
Narcotic-related constipation
Constipation associated with irritable bowel syndrome
Constipation associated with inflammatory bowel disease
Lubiprostone
Lubiprostone
• Derivative of PGE1, but no activity on prostaglandin receptors
• Activates the ClC-2 channel in apical membrane of GI epithelial
cells
• Increases chloride secretion without changing plasma ion
concentrations
• More water is retained in the intestinal lumen
Linaclotide
Linaclotide
• Guanylate cyclase-C receptor agonist (same mechanism as E. coli
enterotoxins)
• Activation of this receptor increases intracellular and extracellular
c-GMP
– ↑cGMPi increases secretion of Cl- and HCO3- into the intestinal lumen
mainly through activation of CFTR – increased intestinal fluid and
accelerated transit
– ↑cGMPi also inhibits luminal sodium absorption by a sodium proton
exchanger
– ↑cGMPo reduces activity of pain-sensing nerve endings – reduced intestinal
pain
Treatment of Inflammatory Bowel Diseases (Crohn’s Disease,
Ulcerative Colitis)
•
•
•
•
•
•
Induce remission
Maintain remission
Minimize use of steroids
Restore/maintain adequate nutrition
Restore/maintain quality of life
Optimize timing of surgical intervention
Pharmacotherapy of Inflammatory Bowel Diseases
• Mild Disease (mainly colon and rectum)
– Mesalamine, Sulfasalazine (inhibition of prostaglandin and leukotriene
synthesis, possibly modulation of B-cell responses and angiogenesis)
• Serious Disease
– Glucocorticoids (acute flares) – prednisone, budesonide (acts locally in GI
tract, 90% first-pass metabolism)
– Azathioprine (chronic therapy)
– Infliximab (Remicade®) (postsurgery/chronic therapy) – humanized
monoclonal antibody directed at TNFα; also causes apoptosis of
inflammatory cells
Pharmacotherapy of Inflammatory Bowel Diseases
• Vedolizumab (Entyvio®) – option approved for use in patients
inadequately treated by immunosuppressants and biologic agents.
• Humanized monoclonal antibody directed against α4β7 integrin
subunit expressed by inflammatory cells.
• Disrupts binding of inflammatory cells to blood vessels in GI tract,
thus prevents lymphocytes from invading GI tract