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3.26.12 Treatment of GI Disorders

3.26.12 Treatment of GI Disorders

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Published by Diana Hylton
GI disorders Tx
GI disorders Tx

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Published by: Diana Hylton on May 01, 2013
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Treatment of GI disorders
 
IC Week 2
Monday, March 26, 2012McCarson
o
 
In antrum of stomach, signaling through absorption of dietaryintake will gate gastrin release which will be modified by parainputs & somatostatin locally
o
 
What drives acid secretion via proton pump1.
 
Signalling from Muscarinic receptor2.
 
ECL cells
release gastrin & histamine
o
 
Inhibit gastric secretion, Reduce amount of acid (antacids)
o
 
Agents that helps establish/maintain gastric layer
Overview of GI Diseases
 
o
 
Disorders principally of either
 
 Altered secretion or altered motility
o
 
Most common secretory disorder is acid-peptic diseasewhich includes:
 
Peptic (gastric & duodenal) ulcer disease [PUD]
 
Gastroesophageal reflux disease [GERD, dyspepsia orheartburn]
 
Hypersecretory states [Zollinger-Ellison syndrome]
o
 
Lifetime prevalence of peptic ulcer is ~ 10%, whileheartburn occurs in about 50% of healthy individuals
o
 
Goals for treatment of acid-peptic disease:
 
1.
 
relieve pain
 
esophageal chemoreceptors
 2.
 
promote healing3.
 
prevent recurrence
o
 
 Anti-ulcer drugs act to:
 
1.
 
neutralize gastric acid2.
 
reduce gastric acid secretion3.
 
enhance mucosal defenses by cytoprotectiveor antimicrobial activity
3 Pathways Regulating Gastric Acid Secretion
PATHWAY MEDIATOR RECEPTORS ANTAGONIST
1)neural
acetylcholine muscarinic anti-muscarinic
2)endocrine
gastrin gastrin-CCK BH
2
blocker
3)paracrine
histamine H
2
H
2
blocker
o
 
 Anti-muscarinic drugs
 
Parasympathetic system
 
 
Agents like atropine will inhibit para drive
 
 
Seen as acute tx or as adjuncts to other therapies(H2 antagonists) if approaches not working
 
 
Relatively weak inhibitors of acid secretion becausethey act at only one site
o
 
Gastrin:
 
No selective CCK antagonists but ultimately gastrinstimulates acid production through histamine. Soblocking Histamine will prevent 
 
Family of peptide hormones formed by gastric mucosalcells
 
Stimulates gastric motility, HCl & pepsin secretion
 
No direct gastrin antagonists
o
 
H
2
antagonists
 
 
Reduce gastrin secretion
 
Block histamine-induced
cAMP & proton pumpactivation (gastric acid secretion)
 
Histamine (via H
2
receptor) enhances parietal cell
 
Affinity for both gastrin & acetylcholine
 
o
 
H2 blockers are more effective than anti-
 
 
Proton Pump Inhibitors
o
 
Benzimidazole compounds
 
irreversibly inhibit parietal cell proton pump, H
+
/K
+
ATPase
o
 
Are
pro-drugs
that are
inactive
at neutral pH
 
 Activated in an acid environment 
(take w/ food)
 
Unstable at a low pH,
to avoid degradation by acid inesophagus & stomach,
dosage forms are supplied asenteric coated granules that dissolve only at alkaline pH
(absorbed in intestine)
 
 
After passing through the stomach, enteric coatingsdissolve & the pro-drug is absorbed in intestines
 
Carried by circulation to the parietal cells, where thedrug accumulates in secretory canaliculi
 
Activated at acid pH & form sulfonamide or sulfenicacid which binds sulfhydryl groups on H
+
/K
+
ATPase
o
 
Preparations include:
 
esomeprazole, omeprazole, lansoprazole,pantoprazole, rabeprazole
o
 
Clinical Use:
 
Most effective drugs for suppressing gastric acidsecretion b/c gastric response to all stimuli isinhibited
o
 
A single daily dose inhibits gastric acid secretion by 95-100% w/o affecting pepsin secretion or gastric motility
o
 
Inhibition of gastric acid secretion persists afterwithdrawal of drug:
 
 
Irreversible inhibitors
: time required tosynthesize new proton pumps (H
+
/K
+
ATPase)
o
 
Generally well tolerated without producing seriousadverse effects
 
o
 
 Adverse effects of PPI:
 
GI effects (nausea, colic, flatulence, constipation, &diarrhea),
 
CNS effects (headache, dizziness, somnolence), &
 
skin rashes
 
with prolonged use diarrhea often occurs due to GITbacterial overgrowth from removal of natural acidbarrier
 
hypergastrinemia occurs in 5-10% of long-term users
o
 
Hepatic metabolism with negligible renal clearance
o
 
Intestinal absorption is rapid, but bioavailability of theabsorbed form depends on activation at gastric acid pH
o
 
Will promote peptic ulcer healing & prevent ulcerrecurrence
o
 
Are often effective in patients unresponsive to H
2
 antagonists
o
 
More effective than H
2
antagonists for GERD or NSAID-induced peptic ulcers
 
H2-Antagonists
o
 
Four Preparations:
 
cimetidine, famotidine, nizatidine,&ranitidine
 
 
OTC preparations
 
inhibit acid secretion for < 6 hours
 
Prescription doses
 
inhibit 60-70% of total 24-hour acid secretion
o
 
Are all equally effective, rapidly & well absorbed orally, &generally well tolerated with few side effects
o
 
Are structural
histamine analogs
that block H
2
receptorsselectively to reduce gastric acid & pepsin secretionwithout affecting H
+
/K
+
ATPase, H
1
, or any other receptors
o
 
Are especially effective against nocturnal secretion whichis largely driven by histamine (i.e., reduced by 90% ascompared with 60-80% inhibition of daytime acidsecretion)
o
 
Relative potency varies over a 50-fold range:
 
 
famotidine > nizatidine = ranitidine >cimetidine
 
o
 
H2-Receptor Antagonists: ADVERSE EFFECTS
 
Are extremely safe with minor & infrequent adverseeffects
 
DO NOT give to pregnant or nursing women
theycross placenta & secreted into breast milk 
 
 
Most common side effects
:
 
diarrhea, headaches, fatigue, myalgias,constipation, & bradycardia
 
 
Mental changes:
 
confusion, hallucinations, & agitation
 
 
may occur w/ IV administration in Elderly orpts w/ renal or hepatic dysfunction
 
Cimetidine:
(longest on the market)
 
 
Endocrine Side Effects:
 
Gynecomastia orimpotence in men, & galactorrhea in women
 
Inhibitis binding of dihydrotestosterone toandrogen receptors & conversion of estrogento dihydrotestosterone.
 
Increases serum prolactin
 
interferes with cytochrome P450 pathways
 
o
 
Clinical Uses:
 
All are equally effective for healing & preventingrecurrence of PUD
 
Given once daily at 
bedtime
to suppress nocturnalacid secretion will produce ulcer healing rates o> 80-90% after 6-8 weeks of treatment 
 
Their use declined markedly following the discoveryof proton pump inhibitors & the
role of 
H. pylori 
inPUD
 
 
20% failure in smokers & elderly
 
Should NOT be used in combo w/ PPI b/c they
 efficacy of by reducing acid activation
 
Combine w/ antibiotics & bismuth for tx of ptsw/ H. pylori infection
 
 
 Antacids
o
 
Directly chelate acid & turn it into water & salt 
 neutralize the acidity:
o
 
Preparation:
 
aluminum hydroxide, calcium carbonate, comboaluminum hydroxide & magnesium hydroxide
 
o
 
Seldom used (more convenient & effective drugs)
 
Act by reducing gastric acidity
 
Inactivating pepsin
o
 
MOA:
 
Are weak bases that neutralize gastric HCl to formsalt & water, & may interfere with absorption of otherdrugs
 
Provide mucosal protection -
stimulates PG synthesis
 
o
 
Aluminum or magnesium hydroxideeither alone, orcombined with NaHCO
3
or a calcium salt 
o
 
A single effective dose given 1 hr after eating neutralizesfor 2 hrs; 2nd dose 3 hrs after eating extend effect for 4 hr
o
 
 Adverse effects:
 
Magnesium salts
Diarrhea 
 
 Aluminum salts
Constipation
 
Cation absorption & systemic alkalosis in renal patients
o
 
Vary widely in neutralizing capacity, taste, & price
o
 
Antacid tablets are generally weak, needed in largenumbers, & not recommended for active peptic ulcers
o
 
Use as needed to relieve pain in esophagitis, peptic ulcer,& GERD
Mucosal Protective Agents
o
 
Protective coating on peptic ulcers
 
Limits exposure to acid & pepsin
o
 
Sucralfate
(
aluminum sucrose sulfate) bindsselectively to necrotic ulcer tissue & acts as a barrier
 
Polymerizes to produce a viscous, sticky gel
adheresstrongly to epithelial cells & ulcer craters in acidenvironment 
 
Effective in healing duodenal ulcers
 
Side Effect 
C
onstipation
 
 
Poorly absorbed systemically & has few adverse effects
 
Requires acid pH for activation
& should not be giventogether with antacids, H
2
antagonists, or proton pumpinhibitors
o
 
Misoprostol
-
methyl analog of PGE
1
 
 
Binds to PG receptors on parietal cells to inhibit acidsecretion
 
b/c NSAIDs inhibit PG formation, mis
oprostol is used
to prevent NSAID-induced ulcers
 
exact mechanism uncertain but may be cytoprotectiveor inhibit histamine-stimulated gastric secretion
 
 Adverse effects:
diarrhea
&
abdominal pain
 
 
may cause abortion
stimulates uterine contractions
o
 
Bismuth subsalicylate
 
(Pepto-Bismol)-
colloidalbismuth
 
Protective coating of ulcers, Antibacterial against H.pylori
 
OTC -- for treating dyspepsia & acute diarrhea
 
Minimal Adverse effects
but will
darken tongue
 
& stools b/c bismuth sulfide formed is a black solid
 Antimicrobial Drugs
o
 
Helicobacter pylori 
Gram-negative bacterium,causes inflammatory gastritis that may lead to pepticulcers
o
 
Single
antibiotic regimens are
ineffective
against H.pylori infection
o
 
Best txt regimen is 10-14 day
“triple therapy”:
 
 
Clarithromycin,
 
500 mg bid
 
 Amoxicillin,
 
1 gm bid
 
Proton pump inhibitor,
 
bid
 
for patients allergic to penicillin, usemetronidazole, 500 mg bid instead of amoxicillin

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