GI Motility Disorders Pharm

Question 1

Opiates - Examples

Answer 1

1) Morphine, Codeine - high abuse potential
2) Loperamide (Immodium) - also anti-secretory properties. Does not cross blood-brain barrier (so no euphoria)
3) Diphenoxylate - can be combined with atropine (formulation called Lomotil)

Question 2

Opiates - MOA

Answer 2

Anti-motility - delayed transit = more time for absorption

1) Binds mu-opiod receptor, activating a Gi protein, which decreases adenylate cyclase activity
2) Low cAMP opens K+ channels, causing cellular hyperpolarization.
3) Hyperpolarization prevents voltage-gated Ca++ channel opening, preventing muscle contraction (peristalsis)

Question 3

Opiates - Uses and Contraindications/ADRs

Answer 3

Uses: Acute and Chronic diarrhea

Contras

1) Abuse potential
2) Cause constipation
3) Bacterial enteritis (actually worsens diarrhea - we want to clear the bacteria ASAP)

Question 4

Bismuth Salicylate (Pepto Bismol) - Uses and Contraindications/ADRs

Answer 4

Uses

1) Indigestion
2) Abd Cramps
3) Traveler’s Diarrhea
4) Controlling Diarrhea

Contras (B = Bismuth, A = ASA):

1) Interferes with Tetracyclines, radiographic studies (B)
2) Don’t use in Children (Reye Syndrome - A)
3) Blackens tongue and stools (B)
4) Anti-coagulant effect (A)
5) Salicylism (tinnitus, nausea, vomiting - A)
6) Interferes with uric acid excretion (A)

Question 5

Bismuth Salicylate (Pepto Bismol) - MOA

Answer 5

Pepto = Bismuth + Aspirin

1) Anti-secretory: Stimulates fluid and electrolyte absorption
2) Anti-inflammatory/anti-bacterial (bismuth is taken up by bugs - toxic to them)

Question 6

Octreotide (Sandostatin) - MOA

Answer 6

Synthetic analog of somatostatin (intestinal D cells), which inhibits the release of VIP (and others). VIP is a mediator of water and electrolyte secretion

Question 7

Octreotide (Sandostatin) - Uses and Contraindications/ADRs

Answer 7

Uses

1) Treatment of Carcinoid Tumors (release VIP) - normally cause flushing, cramping, diarrhea
2) Treatment of VIP secreting tumors

Contras

1) Cholelithiasis - inhibits CCK -> stasis
2) Nausea
3) Abd Pain
4) Injection site discomfort
5) Steatorrhea (fat malabsorption)

Question 8

Adsorbents

Answer 8

Attapulgite, Kaolin/Pectin, Polycarbophil (FiberCon), Cholestyramine (off-label)

MOA: Increases absorption of everything - fluid, electrolytes, but also toxins

ADRs:

1) Obstruction (if inadequate hydration)
2) Constipation
3) Flatulence
4) Heartburn
5) Interfere with drug absorption if taken 1 hr before or 6 hours after med use.

Question 9

Probiotics

Answer 9

Live organisms (Lactobacillus, Bifidobacterium, S. boulardii) given to replenish GI flora when there are deficiencies causing diarrheal issues.

Uses - C. diff, IBD, IBS, necrotizing enterocolitis

ADRs - Flatulence, concern in immunocompromised patients for sepsis.

** S. boulardii is not endogenous, but is a yeast that contains a protease that inhibits intestinal binding by C. diff

Question 10

Fiber

Answer 10

Ex. Vegetables, also Psyllium (Metamucil), Polycarbophil (FiberCon), Methylcellulose (Citrucel)

MOA: (Bulk-forming agent) Retains water in GI lumen, increases transit time

ADRs: Obstruction, abdominal distension, flatulence (make sure adequate hydration)

Effects seen in 3-5 days, maximal at 1 month

Question 11

Docusate Salts (Colace)

Answer 11

MOA: Surfactant for mixing because aqueous and fatty materials in stool, reduces need for straining.

NOT useful for opiates (opiates reduce motility, this does nothing for motility, simply eases passage)

Question 12

Mineral Oil

Answer 12

MOA: Coats the stool to ease passage, decreases absorption of water. Useful to avoid straining

Given PO or rectally. Don’t use for >2 weeks

ADRs: Lipoid pneumonia, foreign-body reactions to oil, decreased fat-soluble vitamin absorption, anal leakage.

Question 13

Lactulose/Sorbitol

Answer 13

MOA: Osmotically active sugars, bring water into intestinal lumen.

ADRs: flatulence, cramps, diarrhea, electrolyte disturbances.

Question 14

Lubiprostone

Answer 14

MOA: Activates CIC-2 Chloride Channel, causing chloride and fluid secretion into GI lumen.

Uses: Idiopathic chronic constipation, IBS-C

ADRs: Nausea, diarrhea, abdominal pain, non-cardiac chest fullness/pressure

Question 15

Linaclotide

Answer 15

MOA: Activates guanylate cyclase-C in the gut, stimulating secretion of fluid by activating apical chloride channels.

Uses: Idiopathic chronic constipation, IBS-C

ADRs: Diarrhea

Question 16

Bisacodyl (Dulcolax, Exlax, Correctol)

Answer 16

MOA: Stimulates the mucosal nerve plexus, inhibiting Na/glucose absorption, causing osmotic diarrhea.

Uses: Constipation, bowel prep - less than 12 hours for activity

ADRs: Severe abdominal cramping, fluid/electrolyte abnormalities

Question 17

Senokot (Senna)

Answer 17

MOA: Unclear - stimulation of Auerbach’s plexus?

Uses: intermittent for constipation, PREFERRED DRUG FOR OPIOD CONSTIPATION - less than 12 hours for activity

ADRs: melanosis coli, severe abdominal cramping, fluid/electrolyte abnormalities

Question 18

Methynaltrexone (Relistor, Alvimopan)

Answer 18

MOA: Blocks mu-opiod receptor, producing relaxation in 1-6 hours.

Uses: Opiod-induced constpation refractory to other drugs (e.g. Senna).

ADRs: Mild GI effects

Admin: SQ injection every other day.

Question 19

Saline Cathartics (Citroma, Visicol, Fleet Enema)

Answer 19

MOA: Mg or Na solutions that induce osmotic diarrhea when used with a liquid diet for 1-2 days.

Uses: NOT for routine use - bowel preps.

ADRs: Fluid/electrolyte abnormalities (Mg accumulation exacerbates renal failure, Na accumulation exacerbates CHF)

Question 20

Polyethylene Glycol (Colyte, Golytely, Moviprep, Miralax)

Answer 20

MOA: Osmotic agents mixed with electrolytes, so we replace the electrolytes lost in diarrhea.

Use: constipation, prep for diagnostic studies (e.g. colonoscopy)

Question 21

Castor Oil

Answer 21

MOA: Metabolized in teh gut to ricioleic acid, stimulating secretion of fluid and decrease in glucose absorption (increases motility).

Action in 1-3 hours.

Contraindicated in pregnancy (induces uterine contractions)

Question 22

Glycerin

Answer 22

Given as a suppository, inducing an osmotic diarrhea. Works in less than 30 minutes

Question 23

TCAs/SSRIs

Answer 23

Useful in treatment of IBS

Question 24

Alosetron (Lotronex)

Answer 24

MOA: 5-HT3 serotonin receptor antagonist, blocking a serotonin receptor that causes intestinal hyperactivity (thus slows intestinal motility).

Use: Approved only for IBS-D in women.

ADRs: Ischemic colitis, constipation

Question 25

Tegaserod (Zelnorm)

Cisapride

Answer 25

MOA: Partial 5-HT4 agonist, causing a prokinetic effect.

Use: Only approved for IBS-C in women under 55 refractory to other therapy.

ADRs: CV ischemia

Contraindications: obstruction, risk of CV disease, depression, anxiety. Discontinue if new abdominal pain, rectal bleeding, or severe diarrhea

*Cisapride is 5-HT4 agonist taken off market for QT prlongation

Question 26

Domperidone

Answer 26

MOA: D2 and D3 antagonist that does not cross the blood-brain barrier.

QT prolongation, thus not approved

Question 27

Metoclopramide

Answer 27

MOA: DAR and 5-HT receptor antagonist in the CTZ.

ADRs: sedation and tardive dyskinesia, especially in elderly women