Anti-Ulcer Drugs. GI. Fitzakerley. Katelyn Rogers. 01.11.10.
1.
Identify diseases treated with “anti-ulcer” drugs, and be able to contrast strategies and objectives for the treatment of peptic ulcer disease with the treatment goals for
hypersecretory diseases and GERD.
Management Objectives:
Those that apply to all uses of anti-ulcer” drugs
Diseases treated with “anti-ulcer” drugs:
Treatment strategies for PUD:



PUD caused by H. pylori, NSAIDs, etc
GERD & NERD (non-erosive)
Hypersecretory states including
hyperacidity/dyspepsia, stress-induced
ulcers in ICU patients, gastrinomas (ZE), &
systemic mastocytosis.

It appears that H. pylori is associated with
PUD, MALT lymphoma, & esophageal cancer.


Eliminate major cause
o Eradicate H. pylori (antimicrobials)
Reduce pain
o Block stimulation of H sec (antimuscarinics, antihistamines)
o Block H sec (proton pump inhibitors-PPIs)
o Buffer acid (antacids)
o Protect the ulcer surface (protective agents)
Treat NSAID-induced ulcers
o Replace prostaglandins (misoprostol)


Heal lesion
Relieve pain
For PUD specifically antimicrobials will:




Decrease possibility of recurrence of dx
Avoid complications
Eliminate maintenance
Prevent development of drug resistance
It is unclear if H. pylori is associated with: Dyspepsia, GERD (which may actually improve when HP is present, so the use of antibiotics may actually worsen GERD), & NSAIDs.
2.
3.
List six different pharmacological treatment strategies for the treatment of PUD & be able to prioritize them according to effectiveness. Be able to give examples of drugs
that fall into each category (HINT: Pay attention to suffixes!) & be able to differentiate from drugs in each group, as well as between drugs in different groups, based on
mechanism of action & side effects. See Table below.
Regarding the treatment of H. pylori infection:
a. Be able to identify the unique properties of the specific antimicrobial agents chosen ie. Understand why the combinations comprising current treatment regimens
were chosen instead of alternatives. See table below.
PPI + AMOXICILLIN for 5 days followed by CLARITHROMYCIN + TINIDAZOLE for 5 days)
PPI + BSIMUTH + TETRACYCLINE + METRONIDAZOLE for 14 days
Therapies change with time, but they always have a mech for pain relief (PPI), combos of antibiotics, & long time course of treatment.
b.
For penicillins, macrolide antibiotics, tetracyclines & metronidazole, define the MOA, antibacterial spectrum, relevant aspects of distribution & major toxicities. See
table and especially footnotes below it.
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4.
Compare and contrast the properties of different classes of drugs that are used to raise intragastric pH (proton pump inhibitors, H2 blockers & antacids). See Table below
and footnotes.
Treatment
Strategies
Eradicate H. pylori
Block stimulation of H+ secretion
Block acid secretion
Buffer acid
Protect the surface
Replace prostaglandins
Drug Groups/
Class
Antimicrobials – must be broad spectrum since H. pylori is gram -.
Antimuscarinics,
Proton pump
inhibitorsa
Antacids
Protective agents
MISOPROSTOL
Main Purpose
Eliminate major cause
Reduce pain
Reduce pain
Reduce pain
Reduce pain
Treat NSAID-induced
ulcers
Drug Names
METRONIDAZOLE/TINIDAZOLE****
MISOPROSTOL (PGE1)
Most effective at preventing & treating PUD!
MOA
CIDAL
Unknown
MOA.
CIDAL
Cell wall
inhibitor
(B-lactam)
STATIC
Prot synth
inhib (50S) to
prevent
tanslocation
STATIC
Prot synth inhib
(30S) prevent
addition of aas
Direct (but
limited)
antimicrobial
activity
Protects ulcer
surface1
BISMUTH=active
ingred.
Difft fxns in
large intestine2.
ALUMINUM HYDROXIDE
CALCIUM CARBONATE
MAGNESIUM
HYDROXIDE
SODIUM BICARB
OTC. Differ greatly b
Good ones are not
absorbed systemically,
but has serious side eff
Buffers acid.
SUCRALAFATE
BISMUTH
SUBSALICYLATE
Effectiveness
ESOMEPRAZOLE/
OMEPRAZOLE,
LANSOPRAZOLE,
PANTOPRAZOLE,
RABEPRAZOLE
Most effective
agents for reducing
intragastric acidity
MANY (Gi,
CNS,
disulfiramlike,
teratogenic
(?), inhib
CYP2C9
Toxicity
Hypersen
s-itivity
GI upset
Drug
interactions
(bc both a
substrate &
inhib of
CYP3A4)
GI upset
Photosensitivity
Brown
discoloration of
growing teeth
(contraindicate
d in pregnancy)
Blackening of
stool (confuse
with GI bleed)
& tongue.
Salycylate
toxicity
(vomiting,
tinnitus,
confusion,
hyperthermia,
resp alkalosis,
metabolic
acidosis)
Side Effects
AMOXICILLIN*
CLARITHROMYCIN**
TETRACYCLINE***
Anti-histamines
BISMUTH
SUBSALICYLATE
ATROPINE
PIRENZIPINE
CIMETIDINE
OTC
Reduce
intragastric
acidityA
Rarely used!
Competitive
inhibitors of
ACh at M
rec.
ATROPINE is
unselective.
PIRENZIPINE
is modtly
selective for
M1, but has
GI effects (so
acid sec can’t
just be M3)
OTC. Esp prevent
nocturnal gastric
acid secretion
Primary: Highly
selective,
competitive
inhibitors of
parietal cell H2
recs.
Secondary: Dec
intracell
cAMPdec in
meal-stimulated
acid secretion.C
Irreversible
inhibitors of ACTIVE
(H/K ATPase) for
49+ h (only in
parietal cell)
SLOW
GASTRIC
EMPTYING &
PROLONG
EXPOSURE
OF ULCER TO
ACID (MORE
SEVERE
THAN H2
BLOCKERS)
Few.
Elderly have decd
clearance &
reduction in vol
of distribution!
 Mental status
changes (IV)
Compete for
renal tubular
secretion w/
weak bases
(MET).
Inhibit gastric
first-pass metab
of ethanol (F),
except
FAMOTIDINE
Unknown affects
in pregnancy.
RAPIDLY given
bradycardia &
hypoTD
None significant.
Rare drug
interactions
Post-therapy
rebound acid
hypersecretion
upon cessatioin.
1-5% have the usual
side effects.
Long term use may
inc risk of hip fx (dec
vit B12, Fe, Ca, & Zn
absorption), resp &
enteric infections, &
ECL cell hyperplasia
bc of the decd
gastric pHinc
somatostatindec
gastrin release, so
more cells are
made.
2
(Sometimes given with
SIMETHICONEantifoaming
agentdecs ST and
pain)
Al3+: Constipating
Mg2-: Cathartic
CaCO2 & NaHCO3
produce CO2 (add
SIMETHICONE)
gastric distention and
bletchin.
ALUMINUM &
MAGNESIUM
HYDROXIDE have a
much lesser incidence
of serious side effects.
Drug interactions
CAUSED by antacids:
-Decd gastric pH
(change absorption)
-Binding of drug in
intestine (dec abs)
-Incd gastric emptying
(dec abs)
-Alkalinize urine
(change elimination)
INTERACTS WITH
TETRACYCLINE.
Treats ulcers induced by
NSAIDs.
-Sucrose sulfatealuminum hydroxide
complex that attaches to
the basement memb of
the ulcer.
-No acid-neutralizing
properties, but may
stimulate mucosal PG &
HCO3, as well as bind
GFs that facilitate repair.
-Limted to stress-related
gastritis since advent of
PPIsc
-Constipation from
aluminum salt
May bind to other meds
& dec their absorption
(see Q 6).
Locally blocks actin of
NSAIDs on the stomach
lining, so they can act
systemically at target.
-Reduces histaminestimulate cAMP
productiondecd H sec,
stim of mucous & bicarb
sec (raises gastric pH &
protects surface)
-Reduce incidence of
NSAID-induced ulcers to
<3% & complications by
50%d
Abortifacient – stimulates
uterine contractions.
Dose related diarrhea,
severe nausea, cramping
abdominal pain (incd
intestinal electrolyte and
fluid sec) in 10-20% of
patients.
*Of the penicillins, AMOXICILLIN is the most effective because of its greater oral availability (compared to Carbenicillin, Piperacillin, & Ticarcillin) & its acid stability (compared to
Ampicillin).
**Of the macrolides, decreased dosing & GI side effects are found with CLARITHROMYCIN/Azithromycin compared to erythromycin. CLARITHROMYCIN is more acid stable than
erythromycin too. Azithromycin has decreased drug interactions bc of no CYP450 interaction, than both CLARITHORMYCIN & erythromycin (this characteristic makes Azithromycin
appear better), but the MIC50 and MIC90 for CLARITHROMYCIN are 0.03 and 0.06 respectively, while Azithromycin is 0.06 & 0.25 respectively. In other words, less
CLARITHROMYCIN is needed to inhibit H. pylori; therefore CLARITHROMYCIN is the BEST of the macrolide drugs.
***Of the Tetracyclines, TETRACYCLINE HAS THE BEST ACTIVITY. Both TETRACYCLINE & Oxytetracycline are incompletely absorbed so give with food & don’t give with antacids
because it chelates the antibiotic.
****TINIDAZOLE is a newer formulation that has a better dosing schedule & less resistance. In obligate anaerobes, METRONIDAZOLE acts as an electron sink; reduction liberates
toxic intermediates, which damage DNA & other macromolecules. 35%-65% of H. pylori are resistant to METRONIDAZOLE. Two significant drug interactions are particularly relevant
to ulcer treatment: METRONIDAZOLE potentiates the anticoagulant effect of WARFARIN; CIMETIDINE decreases the plasma clearance (potentiating the effects of METRONIDAZOLE).
1. BISMUTH disrupts cell wall, causing lysis; prevents adhesion; inhibits urease; coats ulcer, protets from acid & pepsin; stimulates prostaglandin, mucous & bicarb secretion.
2. In lower GI is antimicrobial agent (but limited) & binds enterotoxins. SALICYLATE also inhibits prostaglandin & chloride secretion. Used to treat traveller’s diarrhea.
A. Incd gastric acid secretion results from release of ACh from the neurons of the enteric nervous sytem, which acts on M3 rec on parietal cells (directly incg H+ sec) and ECL cells
(causing release of histamine, which acts on H2 recs to inc H+ sec).
B. Glycopyrrolate may show up on boards but is never used. It is ~ ATROPINE, but less likely to cross BBB.
C. CIMETIDINE net effect is inhibition of all forms of acid secretion: meal-stimulated (60-80%), basal & nocturnal (>90%). Vol of gastric sec & pepsin conc are also reduced. Other
drugs in this class are FAMOTIDINE, NIZATIDINE, RANITIDINE, ROXATIDINE. It’s just that CIMETIDINE is the prototype drug in this class. T1/2=1-4 hours. Presc doses maintain > 50%
acid inhibition for 10 hours, while OTC only 6 hours. Cleared by combination of hepatic metabolism, glom filt, & renal tubular secretion. NIZATIDINE undergoes little first-pass
metab (100% bioavail), while others have ~50%. CIMETIDINE, FAMOTIDINE, & RANITIDINE are available IV for use in treatment of stress-related ulcers. CIMETIDINE is least potent
and requires the largest dose, while FAMOTIDINE is the most potent so only a small dose is required.
D. CIMETIDINE causes in <3% of patients: at high doses, inhibits binding of DHT to androgen rec, inhibits estradiol metab & incs serum prolactin levels; with long term use can
cause gynectomastia & impotence in men & galactorrhea in women. More significant drug-drug interactions are that it inhibits hepatic microsomal drug-metabolizing enzymes
CYP3A4, CYP1A2, CYP2C9, & CYP2D6  incs effects of other drugs.
a. PPIs are useful in the treatment of Zollinger-Ellison syndrome & GERD (conds where H2 blockers are not completely satisfactory). PPIs have only modest efficacy in treating NERD;
they have not been conclusively shown to be superior to either H2 antagonists or antacids in providing symptomatic relief of heartburn. PPIs are acid-labile prodrugs, so they are
administered in acid-resistant formulations (either an enteric coating, or combined with sodium bicarb) that dissolve in the intestine where the drug is then absorbed & circ
throughout the body. The prodrug diffuses preferentially into acidified compartments (ie parietal cell canaliculi), this is where it is converted to active form after protonation. In
fact PPIS require an acid envt in the parietal cell. Short t1/2, however at least 18 hs are required for synth of new pump molecules  significant acid inhibition which lasts ~24 h.
ONLY ONCE DAY DOSING! Full acid inhibition is seen only after 3-4 d after daily meds. Undergo first pass metabolism (CYP2C19 & CYP3A4); with negligible renal clearance.
ESOMEPRAZOLE, LANSOPRAZOLE & PANTOPRAZOLE are available IV for treatment of stress-induced ulcers.
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b. ALUMINUM HYDROXIDE has a SLOW rate of dissolution  slow onset, long duration action, while SODIUM BICARBONATE IS FAST  Rapid onset, short duration of action
DRUG
SERIOUS (BUT RARE)
SIDE EFFECTS
ADVANTAGES
DISADVANTAGES
ALUMINUM
HYDROXIDE
1. efficient
2. low systemic
absorption
1. constipation
2. not very effective
when given alone
MAGNESIUM
HYDROXIDE
1. efficient
2. low systemic
absorption
1. osmotic diarrhea
1. renal insufficiency  hypermagnesemia  CNS and
cardio- toxicity
1. belching, gastric
distention
2. rebound acid
secretion
1. mild systemic alkalosis
2. hypercalcemia in patients with
impaired renal function if taken
with dairy products (milk-alkali
syndrome)
CALCIUM
CARBONATE
1. rapid onset of
action
2. long duration
1. ↓ PO4 absorption (forms aluminum
phosphate precipitates) → ↑ Ca2+
loss → osteomalacia
c. SUCRALFATE requires acidic envt (just like PPI)
to be activated into a viscous paste. Binds up to 6
hours selectively.
d. MISOPROSTOL is rapidly absorbed &
metabolized to active free acid, excreted in urine.
5. Based on an understanding of
pharmacokinetics, explain why timing is critical in
the administration of PPIs.
First PPIS must be administered in the fasting
state, when gastric motility is low. Bc
bioavailability is decd approx 50% by food bc
larger amplitude movts crush the protective
coatings, exposing the prodrugs to the stomach
acid & causing them to be inactivated. Second
PPIs, only inhibit active pumps. Which in a
fasting state, only 10% of pumps are active,
therefore it makes sense to administer PPIs ~1 h
before a meal.
1. severe metabolic alkalosis
2. hypercalcemia in patients with
impaired renal function if taken
with dairy products (milk-alkali
1. belching, gastric
1.
extremely
syndrome)
SODIUM
distension
rapid
onset
of
BICARBONATE
2. short duration of
3. alkalinizes urine
action
action
4. absorption of NaCl causes fluid
retention in patients with heart
6. Explain how MISOPROSTOL facilitates ulcer healing, w/o interfering w/ NSAID failure,
actions ofhypertension
inflammation. or renal
insufficiency
First PGE1 is less involved in inflammation than other PGs & it has a shorter t1/2 (30-40 mins) than NSAIDS. In other words (from notes), the NSAID comes in and blocks PGE1
(leading to incd H+), but MISOPROSTOL can slip in and activate PGE1 again lowering the acidity!
7.
Understand the reason for positive & negative interactions among anti-ulcer drugs, & be able to explain how specific OTC anti-ulcer drugs can alter the absorption &/or
excretion of weak acids & bases. See side effects in Table too.
Remember: SUCRALFATE and PPIS require acidic envt, so ANTACIDS & H2 REC ANTAGS dec efficacy. AND keep OTC meds in mind!
Also: PPIS, H2 BLOCKERS, ANTACIDS all affect luminal pHabsorbance changesurine pH changesexcretion is effected. ANTACIDS chelate TETRACYCLINE.
Gastric Absorption
Excretion
pH<2 (Normal)
pH>4 (high) PPIs
pH<8 (Normal)
pH>8 (Antacids)
Weak acids
More
DECREASE
Less
INCREASE
Weka bases
Less
INCREASE
More
DECREASE
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