GI Perspective

Question 1

Effects of the ANS (PSNS vs SNS) on GI motility?

Answer 1

Parasympathetics stimulate GI motility (rest and digest) while Sympathetics inhibit GI motility (fight or flight)

Question 2

Predominant tone of GI tract smooth muscle?

Answer 2

Parasympathetic (muscarinic CHOLINERGIC)

Question 3

What parasympathetic receptors are found in the GI tract?

Answer 3

M3

Question 4

What is the effect of parasympathetic stimulation on the walls, sphincters, and secretions w/in the GI tract?

Answer 4

1. Walls: contracts
2. Sphincter: relaxes
3. Secretions: increase
   =Overall an increase in GI motility via M3’s (rest and digest)

Question 5

What are the effects of sympathetic stimulation on the walls, sphincters, and secretions of the GI tract? What receptors are involved?

Answer 5

1. Walls: relax via alpha-2 and beta-2 (beta-2 works thru presynaptic inhibition of parasympathetic activity)
2. Sphincters: contract via alpha-1
3. No significant effect on secretions
   =Overall a decrease in GI motility (fight or flight)

Question 6

Effect of ganglionic blockade in the GI system?

Answer 6

B/c PSNS is predominant tone:

1. Reduced GI tone and motility
2. Constipation
3. Decreased gastric and pancreatic secretions

Question 7

Effects of Cholinergic agonists or AchE inhibitors (cholinergic excess)?

Answer 7

DUMBBELS

Diarrhea, Urination, Miosis/muscle weakness, Bronchorrhea, Bradycardia, Emesis, Lacrimation, Salivation/Sweating

Question 8

Effects of muscarinic antagonists (cholinergic deficit)?

Answer 8

Opposite of DUMBBELS + Central Effects
Constipation, Urinary retention, Mydriasis/Blurred Vision, Large Bronchiole Dilation, Tachycardia, Antiemesis, Decreased glandular secretions, Hypo/anhidrosis, Restlessness/confusion/delirium/hallucinations

Question 9

Some medications taken for non-GI conditions have ___________ activity that can lead to _________ as an ADE?

Answer 9

Anticholinergic activity that can lead to constipation as an ADE. But, usually, not every drug w/in a given class has this ADE, or another drug class w/out this ADE can be used to provide the same clinical effect.

Question 10

What are the 4 most significant substances involved in neuronal transmission in the Enteric Nervous System? Why?

Answer 10

These are the 5 that are subject to direct modulation by drug therapy:

1. Ach
2. Dopamine
3. Enkephalin and related opioids
4. Serotonin

Question 11

Role of Ach in ENS?

Answer 11

1. Excitatory to smooth muscle and secretory cells

2. Major neuron-to-neuron (ganglionic) nt in ENS

Question 12

Role of Dopamine in ENS?

Answer 12

It’s a modulatory nt in the ENS

Question 13

Role of enkephalin and related opioid peptides in ENS?

Answer 13

Present in some secretomotor and interneurons in ENS.

1. Inhibits Ach release and peristalsis
2. May stimulate secretion

Question 14

Role of Serotonin in ENS?

Answer 14

Important transmitter or co-transmitter at excitatory neuron-to-neuron junctions in the ENS

Question 15

What is the overall effect of dopamine and by what two mechanisms is this accomplished?

Answer 15

Overall effect= GI relaxant
Mechanisms:
1. Activates D2-R (in LES, stomach)→direct relaxant
2. Activates pre-junctional D2-R→inhibition of Ach release from cholinergic neurons→indirect inhibition of muscular contraction

Question 16

T/F: Anti-dopaminergics are prokinetic?

Answer 16

True

Question 17

Subtypes of Irritable Bowel Syndrome?

Answer 17

1. D-IBS=diarrhea predominant
2. C-IBS=constipation predominant
3. Mixed IBS

Question 18

What is implicated in some cases of IBS? How would this be treated?

Answer 18

Serotonin disequilibrium: Rx with drugs that modify serotonergic signaling

a. Excess 5-HT (hyperactivity)→D-IBS (Tx w/ 5HT3 antagonist)
b. Insufficient 5-HT release (hypoactivity)→C-IBS (Tx w/ 5HT4 agonist)
c. A partial agonist/antagonist would be better for Tx of IBS as antagonists and agonists completelely block/stimulate causing a pt with diarrhea/constipation to develop the opposite

Question 19

Agonisms of 5-HT4 receptors results in what?

Answer 19

Ach release via activation of pre-junctional excitatory 5-HT4-R’s→motility/propulsion

Question 20

Where are 5HT4-R’s located in the GI system?

Answer 20

1. Enteric neurons

2. Smooth muscle

Question 21

Basis for differences in serotonin receptor modulating drug pharmacology?

Answer 21

Selectivity for the type of 5-HT receptor it binds to

Question 22

How do probiotics work in the treatment of IBS? (4)

Answer 22

1. Improve epithelial barrier function
2. Inhibit pathogenic bacteria
3. Acidify colon
4. Improve dysmotility

Question 23

What are 2 types of probiotics?

Answer 23

a. Nonpathogenic strains of Lactobacillus and Bifidobacterium
b. Fermented dairy products, meats, and vegetables

Question 24

Overall success rate of probiotics in the Rx of IBS?

Answer 24

Generally more effective than placebo but not very successful

Question 25

What is a drug target in the treatment of Inflammatory bowel disease (IBD)? Why?

Answer 25

TNF-alpha: b/c it plays a pivotal role in the inflammation associated with IBD

Question 26

Rx of IBD?

Answer 26

Anti-inflammatory agents and, in certain circumstances, TNF-alpha inhibitors

Question 27

What are three opioid receptors in the GI tract? What are there ligands?

Answer 27

1. Delta-R's→Enkephalin 2. Kappa-R's→Dynorphin 3. Mu-R's→Beta-endorphin

Question 28

Where in the GI tract are these 3 opioid receptors located?

Answer 28

In the ENS a. All are located in the Myenteric plexus b. Mu-R's are also found in the Submucosal plexus

Question 29

Effects of GI opioid receptor activation?

Answer 29

a. All 3→Delayed transit time (gastroparesis) | b. Kappa and Mu also cause visceral antinocioception

Question 30

What is the main ADE in the GI system associated with prescription opioids?

Answer 30

CONSTIPATION and incomplete evacuation (hard dry stools)

Question 31

What are two options for opiod antagonists that could be prescribed with opiod analgesics and how do they work?

Answer 31

1. Naloxone - opiod antagonist with low oral bioavailability, so concentration is highest before metabolism - in the GI 2. Methylnaltrexone: quat. ammonium unable to cross BBB, will only act in other parts of the body

Question 32

What is the mc type of preventable ADE in older ambulatory persons?

Answer 32

GI tract events

Question 33

6 types of drug-induced diarrhea?

Answer 33

1. Osmotic diarrhea: drug draws water out 2. Secretory diarrhea: impaired Na+ absorption and Cl and HCO3 are secreted 3. Disordered motility: drugs affecting cholinergic tone 4. Inflammatory diarrhea: direct damage to gastric mucosa or disruption of colonic flora followed by C dif colitis 5. C dif diarrhea: disruption of acid/base environment or epithelial homeostasis 6. Fatty diarrhea: maldigestion/malabsorption (ie weight loss products)

Question 34

Describe pill-induced esophagitis?

Answer 34

A feeling that pill is stuck in throat from esophageal damage; can lead to perforation/hemorrhage if unhealed

Question 35

Risk factors for pill esophagitis?

Answer 35

a. Patient: old age (decreased saliva production), institutionalized, esoph/swallowing disorder, recumbent, neurologic condition, pre-existing GERD or stricture, hiatal hernia b. Drug: gelatin capsules and extended/sustained-release products, concurrent anticholinergics (decrease saliva production)

Question 36

Rate of oral drug absorption depends on what? (2)

Answer 36

a. Drug factors (formulation/physiochemical properties→mucosal permeability) b. Host factors (intestinal villous blood flow, pH)

Question 37

Where are oral drugs absorbed?

Answer 37

Absorption may occur in the oral cavity, esophagus, stomach, or small intestines, depending on the formulation/phyiochemical properties of the drug and the local pH.