GI - constipation/diarrhea/IBS/IBD

Question 1

define constipation and diarrhea in terms of GI motility

Answer 1

• constipation is slow motility of the GI system so we would want to enhance motility.
• diarrhea is enhanced motility and we would want to reduce it (eg- bacteria acting on GPCR–> high cAMP and acts on chloride channels = more secretion). so increased secretion of electrolytes and water will follow.

Question 2

what are some general class of drugs that are used for constipation

Answer 2

laxatives specifically stimulant laxative, osmotic laxative and bulk laxatives.

Question 3

what is a stimulant laxative and what does it do

Answer 3

• bisacodyl (dulcolax), sodium picosulfate, senna, dantron.
• these increase electrolyte secretion and thereby water secretion (by GPCR–> high cAMP–> high chloride).
• they are the most potent laxative and used during colonoscopy. they also increase peristalsis.

Question 4

what are bulk laxatives

Answer 4

• methylcellulose, sterculia, agar bran, ispaghula husk. These are complex carbohydrates.
• there is less risk of having diarrhea with them.

Question 5

what are some general class of drugs that are used for diarrhea.

Answer 5

• drugs that restore fluid and electrolyte balance, inhibit peristalsis–> opioid based drugs.

Question 6

when should laxatives not be used

Answer 6

when there is an obstruction in the bowel because it causes atonic colon (colon’s natural peristalsis activity is diminished and you become dependent on the drug)

Question 7

how do bulk laxatives work?

Answer 7

• bulk laxatives are fibres, either non-fermentable or fermentable and they add bulk to the stool. both attract water, and promote peristalsis.
• some side effects include abdominal distension, bloating and flatulence (gas- seen in fermentable fibres- bacteria are going to digest).

Question 8

what are osmotic laxatives

Answer 8

magnesium sulfate, lactulose, polyethylene glycol.

Question 9

what is magnesium salt (poorly absorbed solute)

Answer 9

• its an osmotic laxative, produces an osmotic load and traps high water content in the lumen.
• should be avoided in small children and patients with renal dysfunction.

Question 10

what is lactulose? (semisynthetic disaccharide- fructose and galactose- also poorly absorbed).

Answer 10

its an osmotic laxative, it takes 2-3 days to work.

Question 11

whats polyethylene glycol (PEG)?

Answer 11

• its an osmotic laxative, has many other industrial uses outside of medicine. it binds water and causes water to be retained within the stool. DOES NOT CHANGE STOOL WEIGHT.
• preferred over lactulose for chronic constipation.

Question 12

what are lubiprostone and naloxegol?

Answer 12

• agents used for opioid related constipation.
• lubiprostone will directly act on chloride channels which will promote fluid secretion. its not recommended for pts who are pregnant.
• naloxegol is Mu (u) receptor antagonists thats pegylated (cause peristalsis). it doesnt cross the BBB and is attached to PEG, so you can prevent constipation while the pt still gets that analgesic effect.

Question 13

what is the pathology of diarrhea?

Answer 13

1) increased GI tract motility+ increased secretion= decreased absorption of fluid and loss of electrolytes (Na+) and water.

Question 14

how do you manage diarrhea?

Answer 14

1) oral rehydration
2) treatment with anti-infective agents (since many infections are bacterial or viral)
3) treatment with spasmolytic or other antidiarrheal agents. (opioids and muscarinic receptor antagonists).

Question 15

what are the main opioids for the relief of diarrhea?

Answer 15

• codeine, diphenoxylate and loperamide (drug of choice for travelers’ diarrhea).
• diphenoxylate/loperamide have low CNS penetration.
• combine loperamide with antibacteral agents to kill the bacterial species that might be causing your bacteria. (you dont want to keep the bacteria longer in your body).

Question 16

whats the mechanism of action for opioids that treat diarrhea?

Answer 16

increase tone and rhythmic contractions of the intestine but diminish propulsive activity.

Question 17

what are some important side effects for opioids that treat diarrhea?

Answer 17

constipation and paralytic ileus which is stomach paralysis.

Question 18

whats the mechanism of action of loperamide (imodium) and diphenoxylate? (preferred over codeine).

Answer 18

they are Mu (u) receptors agonist which inhibit peristalsis in the colon = delay passage of feces= increase absorption of fluid from feces= drying effect on the stool.

Question 19

whats racecadotril?

Answer 19

• its a prodrug of thiorphan which inhibits enkephalinase. (=increase intestinal secretion)
• enkephalins are agonists of delta receptors which inhibit intestinal secretion.

Question 20

what is bismuth subsalicyate (pepro bismol)?

Answer 20

used to treat diarrhea, its an OTC. MOA not well understood. but its thought to contain clays that may act as a bulk forming agents (these bulk agents were used to treat constipation but are also useful when treating diarrhea). bismuth also have anti-secretory and anti-microbial.

Question 21

whats IBS and IBD

Answer 21

IBS is irritable bowel syndrome (characterized by bouts of diarrhea, constipation or abdominal pain).
- IBD is inflammatory bowel disease.

Question 22

what is eluxadoline? and what is its MOA?

Answer 22

• its a drug that is used for IBS with diarrhea. - MOA includes a mixed U and K opioid receptor agonist and delta receptor antagonist that acts on enteric neurons on the GI tract to slow intestinal transit.

Question 23

what is liaclotide? and what is its MOA?

Answer 23

• its a drug that is used for IBS with constipation.
• MOA: acts as an agonist of the guanylate cyclase C receptor in intestinal epithelial cells, which increases cGMP= more chloride and bicarbonate secretion= water follows.

Question 24

what are some forms of IBD that effect the colon or ileum?

Answer 24

ulcerative colitis and crohn’s disease they are autoimmune inflammatory conditions.

Question 25

what are two anti-inflammatory agents for IBS/IBD?

Answer 25

methotrexate and sulfasalazine

Question 26

what is methotrexate and what is its MOA?

Answer 26

its anti-inflammatory for IBS/IBD and its a folic acid antagonist that inhibits DHFR thus inhibiting DNA synthesis. (it has both cytotoxic and immunosuppressant activity).

Question 27

whats sulfasalazine? and what is its MOA?

Answer 27

• its sulfonamide sulfapyridine thats linked to 5-ASA.
  MOA not fully understood but may reduce inflammation by inhibiting leukotriene production, decreasing neutrophil chemotaxis and scavenging free radicals and decreasing superoxide generation.

Question 28

what is one common adverse effect for sulfasalazine?

Answer 28

hypersensitivity.

Question 29

what are two immunosuppressants for IBS/IBD?

Answer 29

ciclosporin and azathrioprine.

Question 30

what is ciclosporin and what is its MOA? and what is the main adverse effect?

Answer 30

• its an immunosuppressant for IBS/IBD.
• it binds to cyclophilin and inhibits calcineurin which decreases IL-2 synthesis and this is needed to activate T cells so by inhibiting IL-2 T cells wont be activated.
• adverse effects include: nephrotoxicity, hepatotoxicity and hypertension.

Question 31

what is azathioprine and what is its MOA? and what is the main adverse effect?

Answer 31

• its an immunosuppressant for IBS/IBD that interferes with purine/ DNA synthesis via metabolism to mercaptopurine.
• adverse effect includes bone marrow depression.

Question 32

what are 4 drugs used for IBS/IBD that are biologics.

Answer 32

infliximab, adalimub/golimumab, vedolizumab, ustekinumab.

Question 33

what are 2 drugs that are biologics for IBS/IBD that work against TNFa?

Answer 33

• infliximab and adalimumab/golimumab. - they both target membrane bound TNFa and are given once every 2 weeks via subcutaneous injection.
• TNFa is a pro-inflammatory cytokine which promote the release of other inflammatory cytokines.
• by targeting TNFa= no more inflammation.

Question 34

what is a drug that is biologic for IBS/IBD that works against a4b7 integrin on T-helper lymphocytes.

Answer 34

• vedolizumab.
• its an antibody that prevents Th lymphocyte interaction with mucosal cell adhesion molecule-1 on GI tract epithelial cells.

Question 35

what is a drug that is biologic for IBS/IBD that works against p40 protein subunit of IL-12 and IL-23?

Answer 35

• ustekinumab.

- they prevent binding of cytokines to their respective IL-12/23 receptors on immune cells to decrease inflammation.

Question 36

whats the relationship between opioids, U/gamma receptors and peristalsis?

Answer 36

opioids bind to U (agonist) to inhibit peristalsis.

opioids also bind to delta (antagonist) receptors decreases secretion.

• eg) naloxegol is Mu antagonist which causes peristalsis.

Question 37

whats the MOA of opioids that treat diarrhea?

Answer 37

increase tone and rhythmic contractions of the intestine but diminish propulsive activity.

Question 38

what are stimulant laxatives?

Answer 38

the only ones that can directly stimulate the intestinal secretions of electrolytes and fluids. they are also called irritants.

Question 39

what are bulk laxatives?

Answer 39

they are the safest but longer acting drugs. they are fermentable (binding bacteria which ferment) or nonfermentable (attracting water in the stools). they provide bulk to the stools and gives your gut something to push on.

Question 40

what are osmotic laxatives?

Answer 40

they are poorly absorbable solutes which create an osmotic load and attract water.