1. 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

2. Nausea and Vomiting Nausea Vomiting
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

4. Input to and Output from the Vomiting Center

5. 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

6. Stimuli for Nausea and Vomiting That May Require Treatment
Motion Sickness
Cancer Chemotherapy/Radiation
Postsurgery/Anesthesia
Pregnancy

8. 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

11. Cancer Chemotherapy/Radiation-Induced Nausea and Vomiting
NK1
5-HT3
5-HT3 antagonists
Ondansetron
NK1 antagonists
Aprepitant
Glucocorticoids
Dexamethasone
Use in combination

12. 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

13. Postoperative Nausea and VomitingH1 M D2
NK1
5-HT3
5-HT3 antagonists
Ondansetron
NK1 antagonists
Aprepitant
Glucocorticoids
Dexamethasone
D2 antagonists
Prochlorperazine
Droperidol
Metoclopramide (also muscarinic agonist)

14. Algorithm for Treatment of Postoperative Nausea and Vomiting

15. 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

16. 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)

17. 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

18. 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

19. 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

21. 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

22. 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

23. Treatment of Constipation (Outpatients)
Increase physical activity
Maintain adequate hydration
Increase bulk in diet
Stimulate motility (when the above prove inadequate and with inpatients)

24. Bulk Agents Commercial Dietary Wheat bran
Fruits and vegetables - pectins, hemicelluloses
Commercial
Metamucil, Fibercon, Citrucel

25. 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, non-absorbable cations or anions; used for bowel preps
Magnesium sulfate, magnesium hydroxide (Milk of Magnesia), magnesium citrate, sodium phosphate (Fleet)

26. Stool Softeners and Stimulant Cathartics
Stool Softeners (relieve straining)
Docusate (Colace, Dulcolax Stool Softener)
Stimulant Cathartics
Bisacodyl (Dulcolax)
Cascara sagrada
Senna (Senecot)

27. 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

28. Lubiprostone

29. 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

30. Linaclotide

31. 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

32. 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

33. 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

34. 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