Part 14: GI Pharmacology Flashcards
the ____ nervous system can modulate digestive processes and drugs that impact this nervous system can have GI effects
autonomic
in addition to influences from the ANS, there is also a ____ network wi the GI tract
localized neuronal
the ____ nervous system regulates GI secretions and motility to facilitate digestive processes
enteric
signals from the ANS are received by the enteric neurons and integrated with other inputs from ___ and ___ hormones
endocrine and paracrine
when does the digestive process begin?
as soon as we think about food
central and ANS inputs to the GI tract increase the secretion of ____ and ____ in anticipation of incoming food
acid and pepsin
____ is released in anticipation of food and acts as a negative regulator to prevent excess secretion of acid in the stomach
somatostatin
which mediators stimulate acid secretion in the stomach?
histamine, Ach, gastrin, pepsin
what is the action of pepsin?
break down peptides
enetric neurons stimulate the secretin of gastrin from ___ cells and release ____ into synapses with several cell types: ___cells, ___cells and ____cells
G cells; Ach; ECL; parietal; D
stimulation of muscarinic receptors by Ach causes the release of ____ from ECL cells
histamine
the histamine released by ECL cells activates H2 receptors on ___ cells
parietal
when histamine stimulates pariental cells, this stimulates the release of ___ into the stomach lumen
protons
parietal cells (in addition to H2 receptors)have ____and ___ receptors which also increase the secretion of protons into the stomach
muscarinic and gastrin
a rise in protons (drop in pH) in the stomach, stimulates ___ cells to inccrease somatostatin secretion which has a negative effect on ____ cells and gastrin release
D; G
outline the 4 steps of acidification of the stomach in eary digestions
- PANS stimulation of enteric neurons stimulate ACh release
- increase secretion of gastrin (G cells) and histamine (ECL cells) triggered by food in the stomach
- gastrin, Ach, and histmaine act on parietal cells, causing secretion of H+ into the stomach lumen, lowering the pH
- the drop in pH causes D cells to secrete somatostatin, which inhibits gastrin release from G cells
what is GERD?
gastroesophageal reflux disease (acid reflux/heart burn): pain and discomfort caused by stomach acid damaging epithelial cells of the upper GI tract
what are some factors that can worsen GERD?
pregnancy, obesity, gravity, certain foods (high fat), overeating or night eating, excessive acid production
do spicy foods cause more acid secretion?
not necessarily, but they can irritate the stomach, worsening the feelings associated with indigestion and reflux
what is PUD?
peptic ulcer disease; occurs when the protective lining of the stomach and small intestine are damaged, exposing sensitive epithelial cells to the acidic environment
what is a possible drug cause of PUD?
NSAIDs
what is a possible bacterial cause of PUD?
H. pylori
how can prolonged NSAID use cause peptic ulcers?
inhibit COX-1 enzymes involved in production of prostaglandins that help protect the epithelial lining
how can H. pylori cause PUD?
causes damage to the stomach lining, and infection leads to peptic ulcers
what is the primary treatment of PUD?
erradicate the cause (bacteria or NSAIDs)
stimulation of muscarinic gastrinand H2 receptors on a parietal cell activates _____pump (aka proton pump) which acidifies the stomach
hydrogen potassium ATPase
stimulation of prostaglandin receptors on stomach endothelial cells causes the secretion of ____ to protect the stomach
mucous
____, which is able to neutralize some of the acid in the stomach is also secreted by epithelial cells by prostaglandin signalling
bicarbonate
what are the 2 main pharmacological approaches to dealing with PUD?
- increase protective barrier
2. reduce acidity by decreasing the amount of protons
what is the general MOA of cytoprotectants?
act to increase the protection of epithelial cells in the stomach and small intestine
what is misoprostol?
a cytoprotectant
what is the MOA of misoprostol?
acts as an agonist of prostaglandin receptors, increasing the production of protective mucous and bicarbonate in epithelial cells
t/f misoprostol can be given in combo with NSAIDs to reduce risk of PUD
t
what are some other ADRs associated with prolonged NSAID use?
nephrotoxicity and cardiovascular risks
what are antacids?
relatively simple inorganic chemical compounds that act by neutralizing acid in the stomach
when calcium carbonate is exposed to acid in the stomach, it makes ____, ___ and ____
CaCL2, CO2 and H2O
t/f the effects of antacids are temporary and provide no influence on acid secretion
t
misoprostol is structurally similar to ____
PGE1
what are some symptoms of antacids?
gas, constipation, diarrhea
antacids have a ___ duration of action
short
to influence acid secretion, we need to influence ___ cells
parietal
what is Ranitidine?
H2 histamine receptor antagonist
what is the MOA of ranitadine in PUD?
competiviely block the H2 receptor in parietal cells, which reduces secretion of protons into the stomach
what is the brand name of ranitadine?
Zantac
histamine receptor antagonists such as Zantac are only selective for ___ histamine receptors
H2
what is the benefit of drugs like Zantac only targeting H2 receptors/
by not targeting H1 receptors (involved in allergies etc.), the Adrs are reduced
rantitidine has been shown to inhibit -___ enzymes
CYP
why are H2 receptor antagonists not as effective as PPIs?
there are multiple inputs to the H-K ATPase proton pump, this is more effective that blocking h2
PPIs bind covalently to the _____, blocking its function and reducing H in the stomach lumen
H-k ATPase proton pump
what drug class has been shown to be most effective at reducing acid secretion in the stomach?
PPIs
____ was the first PPI brought to marjet in the late ‘80’s
omeprazole
what is included in the strucure of omeprazole?
chiral centre, existing as a racemic mix of enantiomers
what is esomeprazole?
formulation of omeprazole that only contains the S enantiomer
how is omeprazole biotransformed to be active?
changes from chiral to achiral
is esomeprazole really better than palin omeprazole?
controversial
when omeprazole enters the parietal cell, its chirality is lost due to ____
the pH of the cellular compartment
omeprazole binds _____ly to the proton pump on pareital cells
covalently
_____ of smooth muscle moves contents through the GI tract
coordinated contraction
the coordinated contractions of the intestinal smooth muscle is regulated by the _____ nervous system and several ___-
enteric; neurotransmitters
input from the parasympathetic nervous sysetm carried by Ach secreting cells sends signals to increase GI secretions which ____ the GI tract and aides in further ___ of the food bolus
lubricates; breakdown of nutrients
to facilitate forward movement, enteric inhibitory interneurons release ______ to relax the smooth muscle cells along the ___ edge of bolus movement
nitrous oxide; forward
excitatory interneurons release ____ to cause muscle contraction behind the bolus to cause ____ propulsion
muscle contraction; forward
____ cells release serotonin which enhances the excitatory signal through the enteric neurons to stimulate muscle contraction to propel the food bolus ____
enterchromaffin (EC); forward
excess 5-HT in the GI tract triggers ____ by stimulating the chemorecptor region in the brain
vommiting
Adrenergic stimulation of the gI tract smooth muscle causes ____
muscle relaxation, slowing gi motility
t/f Ach, NE, 5-HT, DA, NO and neuropeptides are all involved in GI secretions and motility
t
describe how activation of m3 receptors on smooth muscle leads to contraction
stimulation by Ach activates the Gq pathway which increases ip3, wich increases intracellular ca, which increases the interaction of actin and myosin leading to contraction
what happens when the b2 receptors of smooth muscle are activated?
muscle relaxation
how does activation of B2 receptors in smooth muscle inhibit contraction?
inhibits the myosin light chain kinase
what is IBS?
irritable bowel syndrome; a non-inflammatory disease where dysregulation of gi motility leading to either diarrhea or constipation (some people have bouts of both)
is the underlying cause of IBS known/
no
what are the primary goals of treatment for IBS?
managing symptoms
IBS can cause ____ that result in abdominal pain
smooth muscle spasm
for acute diarrhea or consitpation, what are the treatment goals?
indentify the source (remove source if possible) and possible pharm treatment
what is IBD?
Inflammatory bowel disease; where chronic inflammation of the GI tract causes pain and GI transit issues
what is the best target for managing IBD?
the underlying inflammatin
give 2 examples of IBDs
chron’s disease, ulcerative colitis
IBD is typically treated with ___ modulating therapies
immune
presynaptic enteric neurons express what 3 types of receptors all known to modulate Ach release from these neurons
mu opioid, D2, 5-HT4
M3 agonists lead to ____ GI motility
increased
B2 agonists lead to ___ GI motility
decreased
loperamide is a ____ receptor agonist
mu opioid
what is loperimide?
a peripherally restricted opiod with littel analgesic effect
does loperimide cross the BBB?
no
loperimide is used as a ____ agent for short-term use
anti-diarrhea
why does activation of mu opioid receptors lead to decreased GI motility?
Gi coupled receptors, decrease Ca channel opening and therefore decrease Ach release which decreases GI contractility
anticholinergics can ____ (increase or decrease) diarrhea and GI spasm
decrease
give an example of an anticholinergic that could be used as an antidiarrheal
atropine
what is the effect of levodopa on GI motility?
decreased, can lead to constipation
how do dopamine agonists reduce GI contractility?
reduced Ach release from enetric neurons
is the primary management pharm or non-pharm?
non-pharm
what are 2 non-pharm interventions for constipation?
increase hydration and fiber intake
what drug class is most often used to combat constipation?
osmotic laxatives
how do osmotic laxatives promote GI motility?
increase water in the intestine
what are some ADRs of osmotic laxatives?
the pulling of water into the intestine can cause some abdominal cramping and pain
give an example of an osmotic laxative used for colonoscopy prep
PEG (polyethylene glycol)
stimulant laxatives are reserved for what cases?
if other agents have not been ineffective or a faster onset of action is needed
why are stimulate laxatives not routinely used?
they can have longterm ADRs like electrolyte imbalances and dehydration
give an example of a stimulant laxative
bisacodyl
MOA of stimulant laxatives
directly stimulate the smooth muscle in the colon to contract, causing voiding
stimulant laxative act quickly, but cause ___ and __ in the process
cramping and pain
stimulation of 5-HT receptors in the enteric neurons is used to treat ____ (constipation or diarrhea)
constipation
how does stimulation of 5-HT receptors in eneteric neurons help treat constipation?
increases the release of Ach and neuropeptide release to promote GI tract smooth muscle contraction to promote bowel movement
____ was the 1st 5-HT4 receptor agonist, released in the early 2000’s for the management of constipation
Tegaserod
why was Tegaserod removed from Canadian and US market?
apparent increase in risk of heart attack and stroke in clinical trials
what is an alternative 5-HT4 agonist similar to tegaserod that has not been implicated with increased cardiovascular risk?
prucalopride
t/f tegaserod is stil available in the US by special auth
t
ulcerative colitis involves inflammation of the ___
colon
Chron’s disease involves inflammation of the ____
more widespread inolvement of small and large intestines
t/f as severity of IBDs progresses, the treatment options also become more intense, potentially leading to surgery
t
what is 5-ASA?
an aminosalicylate indicated in mild presentations of IBD
5-ASA is most often chosen for mild cases of IBD if the ____ is inflammed
colon
in more severe cases of IBD, more intense immunotherapy such as ____ may be needed
systemic corticosteroids
5-ASA is a class of anti-inflammatory drugs with ____ oral bioavailability
poor
why is it advantageous in that 5-ASA has poor oral bioavailbility?
bc we are trying to target the GI tract, so this way it will be more concentrated in the GI tract
5-ASA has been shown to inhibit ____ enzymes
COX
5-ASA has cellular effects in immune cells to reduce the production of cytokines by interfering with ____ mediated transcription
NF-kB
release of ___ in the GI tract stimulates afferent neurons to the CNS that trigger emesis
5-HT
t/f ant-emetic drugs may act at different locations to reduce the signal received by the vomiting center in the brain
t
give an example of an anticholinergic anti-emetic
scopolamine
give an example of an H1 receptor antihistamine used as an anti-emetic
dimenhydrinate
give an example of a 5-HT3 receptor antagonist used as an anti-emetic
ondansetron
anticholinergic and H1 antihistamines are most effective in blocking input from the vomiting center by the ____ system
vestibular
which classes of agents are best for treating motion sickness? (also good as general anti-emetics)
anticholinergics and H1 antihistamines
5-HT3 receptor antagonists act in the ___ system and the ____ trigger zone, making them useful for chemotherapy N?V
enteric; chemoreceptor trigger
what is scopolamine?
a non-selective antagonist of muscarinic receptors
scopolamine blocks ___ receptors in the vestibular pathway to reduce motion sickness
M1
blocking M1 receptors in the ____ and ____ also blocks emetic input from stimuli other than motion
solitary nucleus and CTZ
what are some systemic ADRs of blocking Muscarinic receptors?
blurred vision, dry mouth
what is the dosage form of scopolamine for motion sickness
transdermal patch
t/f short term use of scopolamine is typically well tolerated
t
t/f scopolamine is more effective as a prophylactic therapy
t
H1 histmamine antagonists can also reduce the development of motion sickness by blocking inputs from the ____
vestibular system
____ is a first generation H1 receptor antagonist similar to those used to treat allergies, but is used to treat nausea
dimenhydrinate
how does dimenhydrinate treat N/V?
blocks H1 receptors in the vestibular system
what is a common ADR of dimenhydrinate?
1st gen, crosses the BBB, causes drowsiness
t/f first gen antihistmamines are also known to block muscarinic receptors, having additional anticholinergic effects
t
t/f 1st gen antihistamines can sometimes have anticholinergic ADRs
t
t/f 2nd gen antihistmamines have far fewer ADRs, but dont have good antiemetic activity
t
ondansetron is typically reserved for patients with ___ induced N?V
chemo
what is the MOA of ondansetron as an antiemetic?
blocks the 5-HT3 receptors in the GI tract and the CTZ reduces input to the medulla and reduces vomiting signal
what are the ADRs of ondansetron?
blocking serotonin in the GI tract causes dysregulation of the GI tract (diarrhea/constipation)
