03-03 GI PHARM Flashcards
REVIEW: Motility physio
- What are the main positive (pro-motility) GI neurotransmitters?
- The main negative ones?
Positive: ACh and Substance P
- Stimulate contraction by ↑ [Ca2+]
Negative: NO and VIP
- Maintain relaxation downstream
- Nice review of mechanism on slide 24.*
neostigmine
- Indication
- MoA?
- Drawback?
- used rarely after surgery for acute colonic pseudo-obstruction or paralytic ileus
- reverisble acetylcholinesterase inhibitor → ↑ ACh bioavailability
- competitive inhib (ACh look-alike)
- problem is that they act too generally throughout the body to be very useful
domperidone
- Indication?
- MoA?
- How is this improvement over older drugs in class (give example)?
- ADRs?
- Prokinetic agent but not approved by FDA, only experimental
- inhibits the inhibition by blocking dopamine (D2) receptors in myenteric plexus
- does not penetrate CNS as did older drugs (e.g. phenothiazines)
- ADRs: 2013 EU study showed ↑ CVD risk
metoclopramide
- Indication(s)?
- MoA?
- ADRs?
Indications
- promotility agent; anti-emetic
MoA
- PRIMARY: stimulates 5-HT4-R on enteric interneurons → ACh release → ↑ gastric emptying + faster transit time thru small bowel via…
- …↑ resting LES tone
- …↑ gastric tone/peristalsis
- …relaxes pylorus
- …↑ duodenal peristalsis
- no effect on secretions or colon contractions
- SECONDARY: inhib’s inhib of dop. at D2-R (like domperidone)
ADRs
- rarely: extrapyramidal SEs
- ↑er risk when co-Rx’d w/ domperidone; in kids/teens
erythromycin
- Indications
- MoA
- ADRs?
Indications
- gastroparesis
MoA
- motilin (re-call = peptide that reg’s MMC) receptor agonist
- enhances upper GI motility (not so much lower GI)
ADRs
- tolerance develops
- antibiotic effects
Re-cap the prokinetic drugs we learned
- basic MoA?
- neostigmine
- acetylcholinesterase inhibitor
- works at enteric neuro-muscular jct
- domperidone
- inhibits the inhibiton of dopamine
- D2-receptor antagonist
- metoclopramide
- 1° 5HT4-R agonist; 2° D2-R antagonist
- erythromycin
- motilin receptor agonist
These accentuate natural rhythm already there
REVIEW: nausea physio
- Name brain region responsible
- receptors involved?
CTZ (chemoreceptor trigger zone)
- previously thought to be area of medulla w/o BBB
- ?evolved to sense toxins
- Now ?loosely organized network → “central pattern generator”
- receptors: 5HT3-R, D2-R, M1-R, CB1-R
phenothiazine
- Indication
- MoA
- similar drugs
- ADRs
An example drug is promethazine
- Indication: nausea in acute emergent situations
- extrapyramidal ADRs too risky for chronic use
- MoA: D2R antagonist
- similar drugs: metoclopramide, domperidone
- hi-dose metoclopramide is really good for chemo-related nausea but higher dose = higher risk for EPS
ondansetron
- Indication
- MoA
- ADRs
ondansetron
- Indication: nausea (esp chemo, radiation, pregnancy and ~post-op)
- same efficacy as metoclopramide
- safer but $$
- MoA: 5HT3-R antagonist
- acts both on GIT’s vagal 5HT3-R (thought to be 1° MoA) and CNS R’s
- ADRs: few, no EPS ADRs like metoclopramide
dronabinol
- Indication
- MoA
- ADRs
dronabinol
- Indication:
- prophylax for chemo n/v
- appetite stim in HIV/AIDS
- MoA: agonizes canabinoid-R’s → appetite
- ADRs: abuse and ADRs “related to complex CNS actions”
diphenhydramine
- indicated for?
- MoA?
- mild-mod motion sickness
- H1 antagonist
scopalamine
- indication?
- ADR?
- motion sickness, vestibular d/o
- Muscarinic antagonists
Chemo anti-nausea Rx is often given as a combo of drugs. What drug is usually given with them?
dexamethasone is most commonly agent in comboination anti-emetic tx
Ginger
- Shown to work for?
- MoA?
Ginger is indicated for
- motion sickness, post-op nausea and morning sickness
- less convincing evidence for chemo n/v
- influences gastric emptying in healthy pts
MoA
- shogaols and gingerols stim saliva, bile and gastric secretions
- some 5HT-3 interaction
- some ginger preperations inhib TXA2 and platlet aggregation
What are the anti-emetic drugs we learned?
- MoA (SparkNotes edition)?
- metoclopramide
- D2-R (dopamine) antagonist
- phenothiazines (e.g. promethazine)
- D2-R antagonist
- ondansetron
- 5HT3-R antagonist
- dronabinol
- canabinoid agonist
- diphenhydramine
- H1 antagonist
- ginger
- shogaols and gingerols stim saliva, bile and gastric secretions
- 5HT-3 interaction
What heartburn/GERD meds did we cover?
Mg- and Al- hydroxides, Cimetidine, omeprazole
Mg- and Al- hydroxide
- MoA
- Most effective preparation
- ADRs
- MoA: direct neutralization of acid
- Al/Mg liquid preperations are the best
- ADRs
- Al(OH)3 - can have constipating effect
- Mg(OH)2 - can have laxative effect
cimetidine
- MoA
- Equally effective sister drugs w/ fewer ADRs
- ADRs
MoA
- H2 receptor antagonist → ↓ basal (e.g. nocturnal) H+ secretion
Sister Drug
- famotidine (brand = Pepcid AC) and ranitidine (Zantac)
ADRs
- P450 inhibition → increases half-life of P450 metabolized drugs
omeprazole
- Indications
- MoA
- ADRs
Indications
- GERD
- PUD (shown more effective at encouraging ucler healing than H2 antagonists)
MoA
- PPIs are pro-drugs that covalently bind the proton pump irreversibly inhibiting it
- major difference betwen the PPIs is their kinetics; equal efficacy otherwise
ADRs
- may inhibit some P450s (warfarin and BZDs)
- ∆s in pH can affect absorption of other Rxs
What diarrhea tx options did we learn?
- MoA SparkNotes
oral rehydration therapy
- fluid repletion
metamucil
- bulk-forming but mech unknown
loperamide (Immodium)
- opiod agonist, 40X more potent at slowing poop than morphine
Pepto (bismuth subsalicylate)
- mech unknown, safe but causes black stools
What IBS treatment options did we cover?
- SparkNotes MoA
alosetron
- 5HT3 antagonist
tegaserod (Zelnorm)
- 5HT4 agonist
alosetron
- Indicated for?
- MoA
- ADRs?
Indicated only for women with IBS-D who have failed other tx
MoA
- 5HT3 receptor antagonist
- recall drugs ending in “setron” are serotonergic
- e.g. ondansetron
- Reduces:
- intestinal motility
- sensitivity to distention
- Theory is that:
- ↓ plasma [5HT] is assoc’d w/ IBS-C and
- ↑ plasma [5HT] assoc’d w/ IBS-D
ADRs
- rare but serious ischemic colitis
- Was pulled off market and then returned in 2002 w/ limited marketing capability
tegaserod (Zelnorm, a.k.a. creepy belly ad drug)
Indicated:
- IBS-C in women
- chronic constipation
MoA
- 5HT4 agonist
- Theory is that:
- ↓ plasma [5HT] is assoc’d w/ IBS-C
- ↑ plasma [5HT] assoc’d w/ IBS-D
ADRs
- heart attack, stroke, unstable angina
- pulled off market for a while
- now only on emergency basis
Available in U.S. under an emergency investigational new drug (IND) process. Emergency situations are defined as immediately life-threatening or requiring hospitalization. Physicians with patients who may qualify can contact the FDA’s Division of Drug Information. The FDA may either deny the request or authorize shipment of Zelnorm® by Novartis.
What IBD tx did we learn?
- sulfasalazine/mesalamine
- prednisone
- budesonide
- azathioprine/6-MCP
- MTX
- infliximab
sulfasalazine/mesalamine
- Indicated for
- MoA
- ADRs
Indications
- Mild-to-Moderate UC
- More effective in UC than Crohn’s
MoA
-
Sulfasalazine: prodrug not absorbed in upper GI tract cleaved by bacteria into
- sulfapyridine ~toxic metabolite AND…
- …Mesalamine (5-aminosalicylic acid, or 5-ASA): active metabolite
- would be absorbed in upper GIT if given PO unless packaged specially
- e.g. Pentasa (PO mesalamine in time-release capsules)
- e.g. Asacol (PO mesalamien in pH-sensitive capsules)
- would be absorbed in upper GIT if given PO unless packaged specially
ADRs
- few b/c not absorbed much systemically?
- nothing in slides
azathioprine/6-MCP
Indications
- mod-to-severe IBD
MoA
- most commonly used immunosuppressives, but take several weeks to kick in
- need steroids to bridge ‘til that time
-
azathioprine is prodrug of 6-MCP
- either works well
- could also consider MTX
ADRs
- bone marrow suppress
- leukopenia
- teratogenesis
infliximab (Remicade)
infliximab (Remicade)
- TNFα inhibitor used to control IBD
- adalimumab (Humira) and certolizumab (Cimzia) are also anti-TNFα used in IBD
constipation drugs basics (not on drug list on first slide)
physical activity, regular b.m schedule, increased fiber and water intake
stool-wetting agents actually have very minimal effect
stimulant laxatives cause mild inflammation
See image
Why is budesonide better than prednisone for mod-to-severe IBD?
extensively removed in first-pass metabolism, therefore can be packaged to be released only in terminal ileum where it acts locally but then is most filtered out by liver before systemic
- pricier
