B5.048 Gastrointestinal Pharmacology Flashcards
most common GI secretory disorders
acid peptic disease
GERD
lifetime prevalence of peptic ulcers
10%
lifetime prevalence of GERD
50%
examples of motility disorders
vomiting
diarrhea
constipation
therapeutic goal of PPIs
inhibit gastric acid secretion
therapeutic goal of H2 antagonists
inhibit gastric acid secretion
therapeutic goal of antacids
neutralize gastric acid
therapeutic goal of mucosal protective agents
acid barrier in necrotic tissue
therapeutic goal of antimicrobial agents
eradicate H.pylori
mechanism of PPIs
benzimidazole compounds that irreversibly inhibit the parietal cell proton pump (H+/K+ ATPase)
covalent chelation
discuss the activation of PPIs
pro-drugs that are inactive at neutral pH
- activation requires an acidic environment (take with meals to stimulate acid secretion)
- unstable at low pH, so degradation in esophagus and stomach is prevented by enteric coating of tablets that dissolve only at alkaline pH
- enteric coating dissolves and pro-drug is absorbed in the intestines
- blood circulation carries pro-drug to parietal cells, where it accumulates in the secretory canaliculi
- finally activated at acid pH and binds to sulfhydryl groups on the H+/K+ ATPase
how to PPIs maintain efficacy with chronic use? aka…how do they get activated when you’re stopping acid secretion
parietal intracellular canaliculi where pro-drug is activated is UPSTREAM from the proton pump target in luminal membrane
names of PPIs
esomeprazole omeprazole lansoprazole dexlansoprazole pantoprazole rabeprazole
why are PPIs the most effective drugs for acid secretion suppression
inhibit gastric response to all stimuli (neural, gastrin, histamine)
inhibitions persists after withdrawal of drug, takes time to synthesize new proton pumps to replace inhibited ones
adverse effects of PPIs
generally well tolerated most common: GI effects CNS effects skin rahses diarrhea due to GI bacterial overgrowth due to removal of natural acid barrier hypergastrinemia in 5-10%
pharmacokinetics of PPIs
hepatic metabolism
renal clearance
H2 receptor agonist preparations
cimetidine famotidine nizatidine ranitidine all equally effective, rapidly and well absorbed orally, and well tolerated
how do H2 receptor agonist preparations differ?
relative potency, dosing is different
famotidine > nizatidine = ranitidine > cimetidine
overall effectiveness of H2RAs
inhibit acid secretion for < 6 hours
inhibit 60-70% of total 24 hr acid secretion
especially effective against nocturnal secretion which is largely driven by histamine
H2RA mechanism
structural histamine analogs that block H2 receptors selectively to reduce gastric acid and pepsin secretion without affecting other parts of the acid secretion pathway
clinical uses of H2RAs
given once daily at bedtime to suppress nocturnal acid secretion
20% failure in ulcer patients who smoke and in the elderly
use has declined since PPIs
when should you not use H2RAs
in combo with PPIs
reduce efficacy of PPIs by reducing acid activation
adverse effects of H2RAs
safe with minor and infrequent adverse effects
should not be given when pregnant or nursing
most common side effects: diarrhea, headaches, fatigue, myalgias, constipation, bradycardia
when can mental changes occur with H2RA use
IV administration in patients who are elderly or have renal or hepatic dysfunction
specific adverse effects of cimetidine (longed H2RA on the market)
gynecomastia or impotence in men
galactorrhea in women
^^inhibits binding of DHT on androgen receptors
interferes with cytochrome p450 pathways for hepatic metabolism of many drugs
types of antacids
aluminum hydroxide
calcium carbonate
combo aluminum hydroxide and magnesium hydroxide
mechanism of antacids
weak bases that neutralize gastric HCl to form salt and water, and may interfere with absorption of other drugs
act by reducing gastric acidity and inactivating pepsin
may also provide mucosal protection by stimulating PG synthesis
why are antacids popular
low cost
rapid action
what are adverse effects associated with antacids
diarrhea - magnesium
constipation- aluminum
cation absorption and systemic alkalosis in renal patients
rebound acid oversecretion
administration of antacids
single effective dose given 1 hr after eating neutralizes for 2 hrs
a second dose given 3 hours after eating extends the effect for 4 hours
common uses and contraindications for antacids
uses: esophagitis, peptic ulcer, GERD
contraindications: active peptic ulcers
mechanism of mucosal protective agents (MPAs)
creates a protective coating on peptic ulcers
limits exposure to acid and pepsin
mechanism of action of sucralfate
binds selectively to necrotic ulcer tissue and acts as a barrier
polymerizes to produce a viscous, sticky gel that adheres strongly to epithelial cells and ulcer craters in acid environment
effective in healing duodenal ulcers
side effects of sucralfate
constipation
poorly absorbed systemically, so few adverse effects
contraindications for sucralfate
required acid pH for activation
do not give with PPIs, antacids, or H2RAs
mechanism of misoprostol
methyl analog of PGE1
binds to PG receptors on parietal cells to inhibit acid secretion
because NSAIDs inhibit PG formation, misoprostol is used to prevent NSAID induced ulcers
exact mechanism unknown
adverse effects of misoprostol
most frequent: diarrhea, abdominal pain
may cause abortion by stimulating uterine contractions
why can misoprostol cause uterine contractions
PGE1 is a potent regulator of uterine muscle tone
what is bismuth subsalicylate?
Pepto-Bismol
colloidal bismuth
mechanism of pepto bismol
protective coating of ulcers
antibacterial against H.pyloru
pepto bismol usage
estimated 60% of American households have it
treat dyspepsia and acute diarrhea
pepto bismol adverse effects
darken the tongue and stool bc the bismuth sulfide formed is a black solid
what are the mucosal protective agents
bismuth subsalicylate
misoprostol
sucralfate
treatment for H.pylori
triple therapy, 10-14 days clarithromycin, 500 mg bid amoxicillin, 1 gm bid PPIs, bid for pts allergic to penicillin use metronidazole 500 mg bid instead of amoxicillin
classes of laxatives
osmotically active
stimulant/irritant
bulk forming
what are saline laxatives
nonabsorbable salts containing magnesium cations (magnesium citrate) or phosphate anions (sodium phosphate)
mechanism of saline laxatives
act by osmotic force to draw water into the intestinal lumen > distended intestines > stimulation of peristalsis
contraindications for saline laxatives
renal insufficiency
heart disease
electrolyte imbalance
diuretic drug co-treatment
mechanism of glycerin
alcohol that acts in the rectum as a lubricant and hygroscopic agent > water retention > stimulate peristalsis
mechanism of lactulose, sorbitol, and mannitol
hydrolyzed to organic acids > acidify luminal contents > draw water into lumen > increase colonic propulsive movement
nondigestible sugars and alcohols laxatives
glycerin
lactulose
sorbitol
mannitol
mechanism of polyethylene glycol (PEG)-electrolyte solutions
poorly absorbed and retain added water by their high osmotic pressure
when is PEG useful?
colonoscopy prep
3-4 liters over 3-4 hours to produce watery diarrhea and remove solid waste
good for complete clearance
preparation of PEG
mixture of: sodium sulfate sodium bicarb sodium choloride potassium chloride in isotonic solution with 60 g of PEG
mechanism of stimulant/irritant laxatives
act directly on enterocytes, enteric neurons, and muscle
induce low grade intestinal inflammation > water and electrolytes accumulate > increase intestinal motility
more useful day to day than PEG
classes of stimulant/irritant laxatives
diphenylmethane derivatives
anthraquinones
ricinoleic acid
diphenylmethane derivative laxative
bisacodyl
bisacodyl administration
enteric coated tablets taken at bedtime and take effect the next morning
swallow without chewing to avoid stomach irritation
examples of anthraquinones
aloe
cascara sagrada
senna
mechanism of anthraquinones
poorly absorbed in the small intestine and require activation in the colon with laxative effects 6-12 hours later
effects of long term anthraquinones use
melanomic pigmentation of colonic mucosa and cathartic colon (colon dilated and ahaustral)
mechanism of ricinoleic acid (castor oil)
local irritant that increases instestinal secretion and motility
now seldom used due to unpleasant taste and potential toxicity
examples of bulk forming laxatives
methylcellulose
lactulose
polycarbophil
function of bulk forming laxatives
add bulk and hold water to expand intestinal contents
requirements for bulk forming laxative use
adequate hydration
without water and movement, can simply make the brick bigger
stool softeners
mineral oil
glycerin suppositories
docusate sodium
use of docusate sodium
prevents straining in hospitalized patients
major antidiarrheal drugs
loperamide
kaolin/pectin
bismuth subsalicylate
somatostatin/octreotide
mechanism of moperamide
Mu agonist relatively selective for intestinal opioid receptors
inhibit ACh release > decrease motility
administration of loperamide
acts quickly on oral admin
peak levels 3-5 hrs after admin
effectiveness of loperamide
40-50 times more effective than morphine for diarrhea
effective against travelers diarrhea
relief of acute, non specific diarrhea
when should you discontinue loperamide
if there isn’t clinical improvement in 48 hours
few adverse effects otherwise
mechanism of kaolin/pectin
kaolin acts by absorbing compounds and presumably binding potential intestinal toxins
pectin increases viscosity of luminal contents
mechanism of pepto bismol when used for diarrhea
inhibits intestinal secretions
management of infectious diarrhea
mechanism of somatostatin/octreotide
inhibits secretion of gastrin, CCK, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, VIP, and 5-HT
reduces intestinal fluid and pancreatic secretion
slows GI motility and inhibits gallbladder
reduces portal and splanchnic blood flow
examples of when nausea and vomiting may occur
pregnancy
motion sickness
GI obstruction
chemo
discuss the pathways involved in emesis
coordinated by medullary vomit center activating efferent pathways in the vagus, phrenic nerves, and spinal innervation of abdominal muscles
mediators of emetic signals
dopamine
serotonin
histamine
substance P
common anti emetic drugs
histamine H1 antagonists dopamine, serotonin, and NK-1 antagonists phenothiazines/ benzodiazepines marijuana derivatives
histamine H1 antagonists
dimenhydrinate
diphenhydramine
cyclizine
meclizine
mechanism of histamine H1 antagonists
produce sedation and antimuscarinic activity
prevent motion sickness
dopamine D2 antagonists
metoclopramide
trimethobenzamine
serotonin 5-HT3 antagonists
ondansetron
granisetron
dolasetron
used during chemo
NK-1 antagonists
aprepitant
fosaprepitant
rolapitant
mechanism of phenothiazines/
benzodiazepines
decrease sensory inputs that drive emesis (anxiety driven)
phenothiazines
chlorpromazine
prochlorperazine
benzodiazepines
lorazepam
alprazolam
marijuana derivatives
tetrahydrocannabinol (THC)
dronabinol
dronabinol use
prophylactic in patients receiving chemo
adverse effects of marijuana derivatives
central sympathomimetic activity in form of marijuana like “highs”
mood changes, laughing, paranoid reaction, and thinking abnormalities
discuss diarrhea as an adverse drug effect
relatively frequent, accounts for 7% of all adverse drug effects
more than 700 drugs implicated
drugs that (more) commonly induce diarrhea
laxatives
GI meds (PIs, H2 blockers)
NSAIDS (3-9%)
SSRIs
important cardio drug that causes diarrhea
ACE inhib
important antidiabetic drug that causes diarrhea
metformin
important antineoplastic drugs that cause diarrhea
irinotecan
doxorubicin
important immunosuppressive agent that causes diarrhea
mycophenolate mofetil (MMF)
drug classes that cause constipation
parasympatholytic agents (reduce PNS tone in the GI) cation containing agents OPIODS cholestyramine NSAIDs vinca alkaloids
important parasympatholytic agents that cause constipation
anticholinergics
diphenhydramine
trimethaphan
important cation agent that causes constipation
iron supplements
mechanism of opioid induced constipation (OIC)
dose dependent and predictable
Mu receptor in the GI directly inhibit Ach release and motility
No tolerance develops
treatment of OIC
stepwise: reduce or eliminate opioid use senna+docusate add bisocodyl add PEG
prevention of OIC
limit opioids to short duration
start bowel maintenance with initial opioid dose
hydration, fiber, movement
