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PHAR 301 > GASTROINTESTINAL DISORDERS > Flashcards

GASTROINTESTINAL DISORDERS Flashcards

1
Q

The Human Microbiota:
1) What does bacteria colonize
2) What are the 5 important functions of bacteria
3) What is an imbalance of gut microbiota associated with
4) How is bacteria better than human cells

A

1) Bacteria colonize skin, mouth, vagina, gut, etc.
- Mainly in large intestine
- Not as much in small intestine or in stomach

2)
- Maturation if the immune-system and gut physiology
- Synthesis of vitamins and metabolites
- Digestions of complex glycan derived from food (fibers)
- Protects from intestinal infection (such as C.difficile)
- Metabolism of xenobiotics due to different P450s

3) Implicated in several diseases

4) Bacteria has more metabolic potential than human cells
- Bacteria will synthesize vitamins and metabolites that we need
- Metabolize dietary fibers and give us energy in return
- Important in immune maturation

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2
Q

Peptic Ulcer Disease (PUD)
1) What area of the GIT does this disease affect
2) What allows ulcers to form
3) What are other contributing factors for PUD

A

1) Upper GIT (stomach, duodenum, lower esophagus)

2) - Decreases barrier function
- Excess acid production

3) - Helicobacter pylori infection
- NSAIDs
- Stress, especially in patients with chronic illness

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3
Q

Helicobacter pylori + Gastric Cancer:
1) Describe the study linking H. pylori infection and gastric cancer

A

1) 1994: 1630 participants infected with H. pylori
- Up to 26.5 years later after regular follow ups and endoscopic check ups
o RESULTS:
♣ Those with H. pylori eradication treatment had a decreased incidence of gastric cancer

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4
Q

Helicobacter pylori + Gastric Cancer:
1) Describe the study linking H. pylori infection and gastric cancer

A

1) 1994: 1630 participants infected with H. pylori
- Up to 26.5 years later after regular follow ups and endoscopic check ups
o RESULTS:
♣ Those with H. pylori eradication treatment had a decreased incidence of gastric cancer

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5
Q

Treatment of H. pylori Infection

A
  • Patients with H. pylori infections require antimicrobial agents to prevent relapse of the infection and thereby ulcers
  • DRUGS (used in combination)
    o Vonoprazen (PPI)
    o Amoxicillin (antibiotic)
    o Claithromycin (antibiotic)
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6
Q

Gatroesophageal Reflux Disease (GERD)
1) What is GERD

2) What does GERD lead to

3) What is Barret esophagus

4) How is GERD commonly treated

A

1) Dysfunctional relaxation of the lower esophageal sphincter
- Allows the acidic gastric contents to reflux into the esophagus

2)
o Inflammation
o Ulcerations
o Bleeding
o Barret esophagus

3) Barret esophagus
♣ Cell lining of the upper GIT thickens
♣ Premalignant condition
* Acid stress can easily develop into cancer

4)
o PPI
o H2 histamine receptor antagonists
o Drugs that increase the tone of the lower esophageal sphincter
♣ DA receptor antagonists

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7
Q

Antisecretory Drugs:
1) What is the direct pathways of antisecretory drug action

2) What is the indirect pathways of antisecretory drug action

3) What are ECL cells

4) Where and what are parietal cells

A

1) These molecules stimulate the parietal cell of the stomach lining to trigger H+ secretion

ACh (from ENS) –> Acts on M3 receptor
Gastrin –> Acts on CCK2 receptors
Histamine
- Acts on histamine receptors
- Sensitizes cell to other stimuli as well
- From ECL cells

2) The molecules are released to stimulate ECL cell of the gastric mucosa to release histamine to act on the parietal cell
♣ ACh (from ENS)
♣ Gastrin

3) ECL cells are neuroendocrine cell found in the gastric glands of the gastric mucosa

4) Parietal cells are found in the in stomach lining
o Has proton pumps responsible for acid secretion into the stomach lumen
♣ Tightly controlled secretion

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8
Q

PPI: Proton Pump Inhibitor
1) Example
2) Action

A

1) Omerprazole
2)
- When it gets to parietal cells, it will cross into acidic vesicles where it will get protonated
♣ Protonated form will not cross membranes
♣ Prodrug converted into active form by acid
♣ Goes and inactivates H+ pump

  • Will inhibit proton pumps on parietal cells
    o Inhibit H+ secretion independent of how the acid secretion is stimulated
    ♣ Histamine
    ♣ ACh
    ♣ Gastrin
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9
Q

H2 Receptor Antagonist:
1) Example
2) Action

A

1) Cimetidine

2) Will inhibit H2 receptors on the parietal cell
o So, histamine will be unable to stimulate the cell
o The cell can still be stimulated to secrete H+ by gastrin and ACh

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10
Q

Muscanaric Antagonist:
1) Example
2) Action

A

1) Propantheline

2) Inhibits ACh receptors (M3) on the parietal cell
o So, ENS cannot stimulate H+ secretion
o The cell can still be stimulated to secrete H+ by gastrin and H2

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11
Q

GPCR:
1) How do GPCRs work in general

A

1) Upon activation of the G-alpha subunit of GPCR by agonist
o G-alpha dissociates from the receptor and G-beta-gamma
o Bound GDP (on G-alpha) is exchanged for GTP
♣ –> Activation of the alpha-subunit
* Activated alpha-subunit then activates other molecules in cell
* One of the outcomes is eventual activation of the proton pump

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12
Q

Drugs that Alter GPCR Activation and H+ Pumping
1) How does ACh activate H+ pumping via GPCR
2) What happens with muscanaric antagonists

A

1) ACh will bind to Gq-alpha subunit bound to GTP
♣ This activated GPCR and causes activation of Gq-alpha
♣ Gq-alpha moves to PLC
* PLC will hydrolyze PIP2
o PIP2 = GLYCEROL + 2 FATTY ACIDS
oPIP2 –> DAG + IP3
♣ DAG activated a kinase that activates the H+ pump

2) By inhibiting ACh action will inhibit H+ secretion from the H+ pump of the parietal cell

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13
Q

Drugs that Alter GPCR Activation and H+ Pumping
1) How does histamine activate H+ pumping via GPCR
2) What happens with H2 receptor antagonists

A

1) Histamine will bind to Gs-alpha subunit bound to GTP
- This activated GPCR and causes activation of Gs-alpha
- Gs-alpha stimulates production of cAMP by activating adenylyl cyclase
- cAMP –> PKA –> H+ pump activation –> H+ secretion

2) If H2 receptor is blocked then none there will be no histamine stimulation of the H+ pump

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14
Q

Drugs that Alter GPCR Activation and H+ Pumping
1) How does prostaglanding inhibit H+ pumping via GPCR
2) What happens with prostaglandin analogs

A

1) When prostaglandin binds to its receptor, it activates Gi-alpha subunit of GPCR
* This prevents the activation of PKA
o This in turn prevents activation of H+ pump –> reducing h+ secretion
* Protective effect on the GIT

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15
Q

NSAIDs:
1) What can NSAIDs cause
2) Action of NSAIDs in stomach environment

A

1) NSAID-associated peptic ulcer disease
2)
♣ Cross membrane easily and are neutral in acid
♣ Once it gets into the cell with neutral pH, it gains a negative charge and gets trapped in the cell
* This causes cell damage

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16
Q

COX-1:
1) When is it expressed
2) What is it involved in
3) What does it produce
4) Blocked by what
5) What does blocking result in (3)

A

1) Constitutively expressed
2) Involved in inflammation
3) Produces the gastric prostaglandins responsible for mucosal integrity
4) Blocked by NSAIDS

5) Decreases [prostaglandin]
o Increases gastric acid secretion
o Decrease bicarbonate/mucous production
o Decrease blood flow

17
Q

COX-2:
1) When is it expressed
2) What is it involved in
3) Blocked by what
4) What does blocking result in

A

1) Induced by inflammatory stimuli
2) Involved in cardiac issues
3) COX-2 selective NSAIDs (ex. Celecoxib)
4) * Carry lower risk of ulcer formation
* Associated with an increase in myocardial infarction and stroke

18
Q

Prostaglandin Analogs:
1) 2 effects of prostaglandins on the GI system
2) Bind to what receptor
3) Example of prostaglandin analog

A

1)
o Cytoprotection
o Decreased acid secretion

2) PGE1 receptor

3) Misoprostol

19
Q

Misoprostol:
1) Effects of misoprostol (4)
2) What can misoprostol be used for

A

1)
o Increases the secretion of mucus
o Increases bicarb secretion
o Enhances mucosal blood flow
o Inhibits mucosal cell turnover
♣ Enhances mucosal defense

2)
- Directly decreases gastric acid secretion
♣ By activating prostanoid receptors on parietal cells
- Can be used to prevent NSAID-induced damage
- Not a first line drug

20
Q

Constipation: Laxatives –> Hyperosmolar Agents
1) What do they do

2) Give an example

3) How and when is this used

A

1) Increase intestinal content osmolarity
♣ This leads to fluid secretion into the bowel
♣ Therefore, leading to bowel movement
* Water flows from an area of low osmotic pressure (more water, less solute) to an area of high osmotic pressure (less water, more solute)

2) Polyethylene Glycol (PEG)

3) PEG is poorly absorbed
♣ Solutions of PEG + electrolytes
* Commonly used for bowel cleaning before colonoscopy
♣ PEG without electrolytes can be used daily for chronic constipation

21
Q

Constipation: Laxatives –> Bulk-Forming Laxatives
1) What are they

2) What do they do

3) What is the paradoxal antidiarrheal effect

4) Give an example

A

1) Bulk-forming laxatives are non-absorbable cellulose-like materials that resemble dietary fibers

2) In the presence of H2O, they hydrate and trigger the defecation reflex
* Fiber-rich diet can also work (it is a non-digestible fiber)

3) Intestinal transit time is reduced
- Paradoxal antidiarrheal effect
♣ Ability to bind excess water can also aid in diarrhea

4) EX: Psyllium + methylcellulose

22
Q

Constipation: Laxatives –> Stimulant Laxatives
1) Example
2) How is the prodrug activated
3) Mechanism of action

A

1) Anthraquinones (Senna glycoside)
2) Converted by colonic bacteria to their active form
* Inactive form has 2 glucose molecules
* Colonic bacteria activates the molecule by removing the glucose molecules

3) Act on the intestinal epithelium
* Increases fluid accumulation
* Increases contraction
- Mechanism is complex
* Seems to involve de-glycosylated active form causing an increase in prostaglandin E2 (PGE2) synthesis

23
Q

INCREASING SECRETION –> Other Agents
Lubiprostone
1) What type of molecule is it
2) What was it thought to do/work
3) How was it later found to work

A

1) Prostanoic acid derivative
2) Was THOUGHT to stimulate type-2 chloride channels (CIC-2) in the SI
* This increase in chlorine rich fluid secretion in the intestine:
o Increases colonic motility
o Softens stool
3) LATER found to bind prostanoid receptors (EP4) on epithelial cells
* Triggers Gs-protein mediated stimulation of adenylyl cyclase
o Increase cAMP activation PKA promotes fluid secretion into lumen

24
Q

INCREASING SECRETION –> Other Agents
Linaclotide

1) Mechanism of Action
2) Analog of what

A

1) Mimics the action of:
* Endogenous guanylin + uroguanylin
o Both guanylate cyclase type C (GC-C) receptor ligands
* Increases the flow of electrolytes + H2O into lumen of GIT
* Increases cGMP production into the serosa
* reduction in visceral hyperalgesia

2) Analog of ETEC heat-stable toxin a (STa)

25
Q

Cl- Secretion and Increasing Fluid Secretion:
1) What was thought to happen by activating Cl- secretion

2) What actually happens

A

1) WHAT WAS THOUGHT: By activating Cl- secretion
o Na+ will follow suit and efflux from the basolateral side to the intestinal lumen
o If the lumen is high in salt concentration, this leads to fluid secretion in the bowel
♣ Water moves from an area of low solute to high solute

2) By activating cAMP production
o Activates PKA –> activation of
- CFTR
* Causing the secretion of Cl-
o Activates PKA –> inhibition of
- NHE3
* Inhibiting the influx of Na+ into the cell

26
Q

BACTERIAL TOXINS: Enterotoxigenic E. coli (ETEC)
1) aka
2) mechanism of action

A

1) travellers diarrhea
2) Stimulates GC-C
* Converts GTP –> cGMP
o cGMP
- Blocks PDE (converts cAMP ATP)
- Activates PKGII (activates CFTR)

27
Q

BACTERIAL TOXINS: Cholera toxin AND E. coli Heat-labile toxin (LT)
1) Mechanism of action

A

1) Triggers Gs-protein mediated stimulation of adenylyl cyclase

28
Q

Cystic Fibrosis Patients:
1) What is the mutation found in CF patients and its link to constipation

2) If you were to use linaclotide or misoprostol, would it work to increase fluid secretion

3) What drug is useful in CF patients

A

1) CFTR mutation in CF patient
o No fluid secretion of mucous membranes
o Therefore, can easily suffer from chronic constipation

2) Expected to work less
* They work to stimulate CFTR
* But if CFTR is non-functional then its stimulation wouldn’t be effective
o Therefore, is blocking of NHE3 and PDE enough to cure the constipation in CF patients?
* Or is CFTR activation just that important

3) Tenapanor is useful in constipation in CF patient to block the influx of Na+

29
Q

Opioid-Induced Constipation: (OIC)
1) What do opioids act on and what does this result in

2) by decreasing motility, what does it result in

3) whats a major side effect of opioids

4) what is used to treat + prevent OIC (type of drug)

5) What’s an example of this drug

A

1) Opioids act on enteric neurons to:
o Decrease secretion
o Promote fluid reabsorption from the lumen

2) Opioids decrease motility resulting in slowed transit through the GIT
o Greater time allowed for fluid absorption
o Drying of fecal mass

3) constipation

4) Opioid antagonists

5) Naloxegol

30
Q

Naloxegol:
1) what is Naloxegol
2) Why is its structure crucial in its action vs other opioid antagonists

A

1) Poly(ethylene glycol)-functionalized derivative of naloxone (narcan)
* Naloxone used to reverse opioid OD

2) This poly(ethylene glycol) makes the molecule unable to cross the BBB and act on the CNS
- Remains in the periphery so no addiction

31
Q

Diarrhea: Opioid Agonists –> LOPERAMIDE
1) Why is loperamide different to other opioid agonists
2) What effect does loperamide have on the GIT and what happens at high doses
3) When should loperamide not be used and why

A

1) Specific antidiarrheal agent that does not cross the BBB acts in periphery

2) Antisecretory effect mediated by mu-receptors
o At higher dosage, loperamide also decreases motility

3) Should NOT be used in symptomatic treatment of diarrhea causes by enteric organisms
* EHEC, C.diff, Shigella
* Because these infections induce toxins in the gut
* So, slowing the motility of the gut can promote their absorption and be dangerous

32
Q

IBD: Inflammatory Bowel Disease
1) What kind of disease is IBD and is it curable
2) What are the 2 main manifestations of IBD
3) What is IBD associated with

A

1) Chronic + incurable disease ever-increasing number of cases
2) Ulcerative colitis + Crohn’s Disease
3) Deregulated immune response directed towards some gut bacteria
♣ Responds poorly to bacteria that wouldn’t normally elicit a response
- Microbial imbalance in the gut

33
Q

IBD:
1) What is the treatment of IBD

A

1)
o 5-aminosalicylates (5-ASA)
o Corticosteroids
o Immunosuppressives
o Biologics

34
Q

IBD: Using biologics as treatment
1) What antibody is used
2) Why would patients lose response to the antibody
3) What additional therapies introduced

A

1) Infliximab (anti-TNF-alpha)
2) suboptimal drug exposure (caused by immunogenicity
3) Vedolizumab + Ustekinumab

35
Q

What is immunogenicity caused by suboptimal drug exposure?

A

Immunogenicity occurs when the immune system in an animal administered a drug recognizes it as foreign and generates a humoral and/or cellular immune response.

36
Q

1) What is Vedolizumab
2) What is Ustekinumab

A

1) Alpha-4-beta-7 blocker
- Prevents T-cell trafficking to the gut

2) Antibody blocking the p40 subunit of IL-12 + IL-23

37
Q

IBD: Using 5-ASA as treatment
1) Example
2) What is the unconjugated version of this example
3) Why is unconjugated form no longer given
4) What was done to resolve this

A

1) Sulfasalazine
2) Mesalamine
3) Mesalamine is rapidly absorbed in the jejunum
- Allowing only 20% to reach terminal ileum + colon to have action

4) Sulfasalazine is a prodrug that gets converted to mesalazine + sulfapyridine by gut bacteria
♣ Sulfapyridine is responsible for many side effects
♣ 5-ASA is responsible for the efficacy in IBD treatment

38
Q

IBD: Using glucocorticoids as treatment
1) Why are glucocorticoids used
2) Conventional examples of glucocorticoids
3) 2nd generation example of glucocorticoids
4) Long term use of glucocorticoids (recommended?)

A

1) Used to reduce inflammatory response of IBD

2)
o Prednisone
o Prednisolone

3) Budesonide

4) Long-term corticoid steroid use with either conventional or budesonide is not recommended

PHAR 301 (11 decks)

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