Lecture 17 part 2 (laxatives)

Question 1

What is constipation and causes

Answer 1

Difficult passage of hard or infrequent stools
Causes: diet, pregnancy, drugs (opioids, aluminum containing antacids, or iron), and GI, metabolic, or neurological disorders

Question 2

Treatment of constipation

Answer 2

Dietary changes (increase intake of fiber and fluids) or laxatives

Question 3

Function of Hyperosmolar agent laxatives

Answer 3

ex. Polyethylene glycol (PEG)
Increases intestinal content osmolarity leading to an accumulation of fluid in colon

Question 4

Uses of Hyperosmolar agent laxatives

Answer 4

ex. Polyethylene glycol (PEG)
Bowel cleansing before a colonoscopy or daily for chronic constipation

Question 5

What are Bulk forming laxatives

Answer 5

ex. Psyllium and methylcellulose (Metamucil)
Nonabsorbable cellulose-like materials that resemble dietary fiber

Question 6

Function of Bulk forming laxatives

Answer 6

ex. Psyllium and methylcellulose (Metamucil)
1) Reduce intestinal transit time
2) Anti-diarrheal effect from binding excess water
Compounds hydrate in presence of water and swell to form a pliable soft mass that activates defecation reflex

Question 7

What are Stimulant laxatives

Answer 7

ex. senna glycoside
Poorly absorbable compounds that can reach the large intestine

Question 8

Function of Stimulant laxatives

Answer 8

ex. senna glycoside
Increase fluid accumulation and promote smooth muscle contraction

Question 9

Mechanism of Stimulant laxatives

Answer 9

Increases prostaglandin E2 synthesis stimulating fluid secretion

Question 10

Mechanism of Lubiprostone

Answer 10

Binds to prostanoid receptors (EP4) on epithelial cells–>triggers GPCR stimulation of adenylyl cyclase–>increase in intracellular [cAMP]–>activates Protein Kinase A–>Protein Kinase A opens the CFTR chloride channel and inhibits Na+ influx into the cell by NHE3
Same mechanism as Misoprostol
By osmosis, water accumulates into the intestinal lumen

Question 11

Bacterial cause to diarrhea

Answer 11

Enterotoxigenic E. Coli (ETEC) secretes
Heat stable toxin (STa)–>causes Traveler’s diarrhea
Heat labile toxin (LT)–>causes constitutional irreversible activation of EP4 (stimulates water release into lumen)

Question 12

Mechanism of heat stable toxin (STa) that causes Traveler’s diarrhea

Answer 12

STa is a peptide agonist of guanylate cyclase type C receptor
STa triggers synthesis of cGMP–>cGMP inhibits breakdown of cAMP and activates Protein Kinase GII–>Protein Kinase A and Protein Kinase GII open CFTR channel–>release of water into intestinal lumen via osmosis

Question 13

Function of Heat stable toxin (STa) analog

Answer 13

ex. Linaclotide
Mimics action of Heat stable toxin a, increasing fluid and electrolyte secretion into intestinal lumen

Question 14

When to use Heat stable toxin analog

Answer 14

ex. Linaclotide
Leads to a reduction of visceral hyperalgesia (pain)
Treats irritable bowl syndrome (IBS) and chronic constipation with unknown cause

Question 15

Advantage of Linaclotide structure

Answer 15

Stable to protease-meduated degradation
Has 3 disulfide bridges–>cyclic peptide

Question 16

Function of opioids on diarrhea

Answer 16

Decrease fluid secretion and promote fluid reabsorption from lumen
Decrease motility, resulting in slowed transit time through GU tract, allowing for greater fluid absorption

Question 17

What to use to prevent opioid induced constipation (OIC)

Answer 17

Opioid antagonists
ex. Naloxone and Naloxegol (has polyethylene glycol so can’t cross BBB)

Question 18

Treatment for diarrhea

Answer 18

Opioid agonists
ex. loperamide
Decreases motility (at high doses, do not use for bacterial infection) and has antisecretory effect mediated via mu-opioid receptors
Decrease secretion and promote fluid reabsorption

Question 19

2 manifestations of Irritable Bowel Disease (IBD)

Answer 19

1) Ulcerative colitis (UC), continuous and uniform inflammation in large bowel
2) Chron’s disease (CD), patchy inflammation throughout small and large bowel

Question 20

What is Irritable Bowel Disease (IBD)

Answer 20

Deregulated immune response directed towards some gut bacteria and a microbial imbalance (dysbiosis) in the gut

Question 21

Treatment for IBD

Answer 21

5-aminosalucylates (5-ASA), corticosteroids, immunosuppressives, and biologics (tumor necrosis factor antagonist)

Question 22

Symptoms of IBD

Answer 22

Bloody bowel movements, abdominal pain, weight loss, and fatigue

Question 23

Function of 5-ASA

Answer 23

ex. Sulfasalazine (prodrug)–> Mesalazine (active form)
Prevent absorption of 5-ASA in proximal GIT, increase delivery to colon

Question 24

Second generation Glucocorticoids for IBD

Answer 24

ex. prednisone and prednisolone or
second gen: Ileal release budesonide in CD and colonic release budesonide MMX in UC