Diarrhea Pharmacology

Question 1

Accurate diagnosis of diarrhea must rule out the following two conditions which are not considered diarrhea since feces output is typically < 200g/day:

Answer 1

Fecal incontinence: involuntary passing of rectal contents, commonly associated with neuromuscular, or structural anorectal disorders.

Pseudo-diarrhea: frequent passages of small amounts of feces caused by rectal urgencies or feelings of incomplete rectal evacuation

Question 2

Narcotic Member Names

Answer 2

Diphenoxylate, difenoxin and loperamide

Question 3

Narcotics MOA

Answer 3

All opioid narcotics inhibit GI motility, decrease secretion and absorption secondary to stimulation of opioid receptors within the enteric nervous system.

Decreasing GI motility allows enough time for water, nutrients and electrolytes to be absorbed from the intestine, thereby alleviating symptoms of diarrhea.

Question 4

Major opioids receptors (µ, δ and κ) are generally _____ and their stimulation leads to

Answer 4

Major opioids receptors (µ, δ and κ) are generally inhibitory and their stimulation leads to decrease intracellular cAMP, increase K+ conductance, decrease intracellular Ca2+ and hyperpolarization.

These actions amount reduced contractility of smooth muscles within the GI and subsequent decrease in motility.

Question 5

Actions of the opioid receptors

Answer 5

The µ receptor affects intestinal motility, δ receptor affects intestinal secretion, absorption is modulated by both µ and δ.

Question 6

_____ is rapidly metabolized to its active metabolite _____ after an oral administration.

Answer 6

Diphenoxylate is rapidly metabolized to its active metabolite difenoxin after an oral administration.

Both diphenoxylate and difenoxin are more potent than morphine for treatment of diarrhea.

Question 7

Why are small doses of atropine commonly added to the opioids?

Answer 7

CNS effects (albeit at very high doses) can occur with use of both diphenoxylate and difenoxin as a result, the risk for addiction and abuse associate with their use is significant

Small doses of atropine are occasionally added to these drugs as a way to discourage deliberate overdose or abuse.

Question 8

Narcotics ADES

Answer 8

Constipation, toxic megacolon, CNS effects.

Anti-cholinergic effects (blurred vision, xerostomia etc.) may occur due to the included atropine.

Question 9

What drug increases anal sphincter tone?

Answer 9

Loperamide

Question 10

Loperamide MOA

Answer 10

In addition to stimulating µ receptors in the GI, loperamide also stimulates Gi receptor which counter the cholera and E. coli – induced increase in cellular cAMP that leads to diarrhea.

More effective in treating diarrhea than diphenoxylate

Question 11

One plus of using Loperamide for constipation

Answer 11

Poor CNS penetration (a plus).

Lacks significant abuse potential, has low adverse effect profile and is available over the counter.

Question 12

Clinical Application of Loperamide

Answer 12

Effective against traveler’s diarrhea (either as a monotherapy or in combination with antibiotics).

Question 13

Loperamide ADES

Answer 13

Not recommended for use in children under 2

CNS depression may occur in case of overdose

Question 14

Bile Acid Sequestrate Members

Answer 14

Cholestyramine, colestipol and colesevalam

Question 15

Bile Acid Sequestrates MOA

Answer 15

Bind and form complexes with bile acids and some bacterial toxins thereby facilitating their excretion.

If allowed to accumulate in the GI, bile salts usually stimulate excessive water and electrolyte secretion in the colon leading to diarrhea.

Question 16

Bile Acid Sequestrates Clinical Applications

Answer 16

Treatment of bile acid-induced diarrhea as in patients with resection of distal ileum – where excess bile salt is delivered to the colon as a result of decrease enterohepatic circulation.

Question 17

What drug is effective in treating mild antibiotic-induced diarrhea?

Answer 17

Cholestyramine

Question 18

Bile Acid Sequestrates ADES

Answer 18

May cause steatorrhea, depletion of fat-soluble vitamins (ADEK) with corresponding manifestations of deficits e.g. night blindness(with vitamin A defficiency), bleeding (with vitamin K deffiency)

In patients with extensive ileal resection, steatorrhea is present secondary to significant bile salt depletion. Thus use of cholestyramine in such patients will aggravate diarrhea instead.

Question 19

Minerals Members

Answer 19

Attapulgite and kaolin

Question 20

Minerals MOA

Answer 20

Attapulgite (a magnesium-aluminum disilicate) and kaolin (a hydrated aluminum silicate) are extremely hygroscopic and avidly bind water within the GI tract.

Both attapulgite and kaolin can also bind to endotoxins, nutrients and even other drug molecules within the GI.

Question 21

A mixture of _______ is available over the counter for treatment of mild diarrhea.

Answer 21

A mixture of kaolin and pectin (a plant polysaccharide) is available over the counter for treatment of mild diarrhea.

Question 22

Minerals ADEs

Answer 22

Well tolerated.

May decrease absorption of nutrients and other drug molecules with the GI tract.

Question 23

What drugs are suitable for diarrhea associated with irritable bowel syndrome?

Answer 23

Plants extracts and minerals

Question 24

Plant Extracts Members

Answer 24

Carboxymethylcellulose, pectin, calcium polycarbophil (not a plant extract but fit this category otherwise)

Question 25

Plant Extracts MOA

Answer 25

Hydrophilic, resistant to enzymatic break-down within the GI, absorb water and increase stool bulk.

Calcium polycarbophil absorbs up to 60 or so times its own weight in water.

Question 26

Plant Extracts Clinical ADES

Answer 26

May also bind to nutrients, and other drug molecules within the GI thereby decreasing their absorption.

Question 27

Bismuth Subsalicylate MOA

Answer 27

Has anti bacterial (H. pylori), anti inflammatory effects, as well as antacid effects

Decrease hypersecretion, stimulate absorption, slow hyper-motility of the stomach

Question 28

What drug is used prophylactically against traveler’s diarrhea?

Answer 28

Bismuth Subsalicylate

Question 29

Bismuth Subsalicylate ADES

Answer 29

Black stool and black tongue

Question 30

Clonidine MOA

Answer 30

Stimulates alpha-2 adrenergic receptors on enteric neurons and enterocytes, inhibiting secretion of fluids and electrolytes as well as increasing intestinal transit time.

Question 31

What drug is effective against diabetic chronic diarrhea where autonomic neuropathy may lead to loss of adrenergic innervation in the GI?

Answer 31

Clonidine

Question 32

What drug is effective in patients with diarrhea caused by opioid withdrawal?

Answer 32

Clonidine

Question 33

One main ADE of Clonidine

Answer 33

Can cause severe withdrawal syndrome characterized by hypertensive crisis.

Question 34

Somatostatin (grow hormone inhibiting hormone), octreotide MOA

Answer 34

Inhibition of hormone secretion (serotonin, gastrin, VIP, insulin etc.)

Question 35

Why is octreotide commonly chosen over somatostatin?

Answer 35

Somatostatin itself is rarely used clinically because of a very short half-life (few minutes). Octreotide a synthetic analog with a longer plasma half-life is a better alterative.

Question 36

Clinical applications of somatostatin and octreotide

Answer 36

Effective against secretory diarrheas (chemotherapy-induced diarrhea, diarrhea associated with HIV, and diabetes associated diarrhea)

Effective in managing the dumping syndrome seen in patients after gastric surgery

Question 37

Somatostatin and Octreotide ADES

Answer 37

GI cramps, hypothyroidism, and headaches