GI Pharm Flashcards
4 signalling molecules that regulate GI motility
Contraction: ACh, Substance P
Relaxation: VIP, NO
what do pro kinetic agents do?
MODULATE rather than mediate motility (regulate ACh activity - either release more or make it longer lived)
4 classes of prokinetic agents
cholinergic agents
dopamine antagonists
serotonin agonists
macrolides
neostigmine
not very useful now –activity is too diffuse
Mech: reversible inhibition of acetylcholinesterase
domperidone
Dopamine D2 receptor antagonist - inhibits dopamine in myenteric plexus but does not penetrate the BBB/CNS
inhibits gastric motility –> reduces lower esophageal and intragastric pressure by reducing ACh release
phenothiazine
classic dopamine antagonist. works for GI but produces extrapyramidal side effects
metoclopramide
5HT4 receptor activation - on interneurons –> to stim ACh release
effects on GI tract –> increased gastric emptying and decreased transit time through duodenum, jejunum & ileum
secondary activity @ D2R
which medication is acts at the motion receptor?
erythromycin
erythromycin
macrolide antibiotic; motilin agonist –> enhances upper GI motility w/ little or no effect in the colon
useful for gastroparesis
utility limited by tolerance and antibiotic effects
ghrelin
effect: increased gastric movement
possibility for future drug development
chemoreceptor trigger zone
area of the brain that lacks BBB – can monitor blood and CSF for toxicants
central pattern generator
neurons coordinating complx series of events that occur during emesis
name 3 dopamine receptor agonists for antiemesis
phenothiazine, metoclopramide, domperidone
which antiemetic is most effective for chemo-induced nausea?
high dose metaclopramide
ondansetron
ondansetron
5HT3R antagonist for nausea (esp originating in the gut)
mech: binds to 5HT3R on vagal neurons lining GI tract –> block signal to vomiting center in the brain –> prevent nausea and vomiting
dronabinol
cannabinoid useful prophylactically for cancer chemo-related nausea
sim appetite
potential for abuse
diphenhydramine
histamine H1 antagonist, useful in mild-moderate motion sickness
what is the most commonly used agent in combination anti-emetic therapy?
dexamethasone
nature’s antiemetic
ginger!
definitely works for motion sickness, morning sickness, post-op, unclear about chemo-induced
diarrhea tx
oral rehydration therapy
some pharmacotherapy options: bulk forming agents, clays, bismuth, opioids, alpha-2-adrenergic agonist
metamucil
bulk forming agent, unknown MOA
kaopectate
clay for diarrhea tx, binds water avidly
loraperamide
antidiarrheal agent, opioid
limited ability to enter CNS, safe
tx for mild constipation
fiber rich diet, increased fluid intake, increased physical activity, development of bowel habits
antacids - MOA, types, side effects
neutralize secreted acid (from proton pump) –> raise pH –> inactivate pepsin
Aluminum or magnesium hydroxide
- aluminum –> can cause constipation
- Mg –> has laxative properties
omeprazole
PPI for GERD
prodrug. covalent and irreversible binding to pump –> inhibits.
safe and well tolerated for short term use (though increased risk of pneumonia
risks of long term use: C. diff, fractures, acute interstitial nephritis
alosetron
5HT3 receptor antagonist for IBS-D in women –> reduces motility and intestinal sensitivity to distension
withdrawn from market b/c severe GI side effect os ischemic colitis
now allowed again for refractory IBS-D pts
lubiprostone
for IBS-C in adult women, chronic idiopathic constipation, opioid-induced constipation
MOA: mimicks prostaglandin, involves Cl- channels
linaclotide
for IBS-C, CIC
MOA: guanylate cyclase-C –> increases [cGMP] –> increases [Cl-] in intestinal lumen –> increase in intestinal fluid and faster transit
how do we currently approach medical tx for IBD?
anti-inflammatory, b/c we don’t understand the disease yet
try to tx the effected area w/out too much systemic effect
sulfasalazine
for mild/moderate UC (less useful in Crohn’s)
MOA: anti-inflammatory
prodrug- prevents absorption in stomach or small intestine
difference b/t sulfasalazine and mesalamine
mesalamine mostly absorbed in upper GI tract - doesn’t get as much to the colon where it is needed
budesonide
locally active glucocorticoid for oral tx of mild-moderate Crohn’s involving ileum and/or ascending colon
high first-pass effect on liver
integrins
possible target for future tx of IBD w/ antibodies
infliximab
anti-TNFalpha mAB for tx of refractory CD and UC – formation of regulatory macrophages w/ immunosuppressive properties, including production of anti-inflammatory cytokines
possible induction of neutralizing antibodies (“anti-drug antibodies”/ANA) –> loss of response
