125 terms

Anti-Ulcers

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H2-antihistamines
"DINEs"

Cimetidine (Tagamet®)

Famotidine (Pepcid®)

Ranitidine (Zantac®)

Nizatidine (Axid®)
Proton Pump Inhibitors (PPIs)
"PRAZOLEs"

Omeprazole (Prilosec®)

Esomeprazole (Nexium®)

Lansoprazole (Prevacid®)

Dexlansoprazole (Dexilent®)

Pantoprazole (Protonix®)

Rabeprazole (Aciphex®)
Prokinetic agent
Metoclopramide (Reglan®)
Prostaglandins
Misoprostol (Cytotec®)
Which classes of anti ulcers decrease gastric acid secretion
1. H2-antihistamines

2. Proton Pump Inhibitors (PPIs)
Which medications increase gastro-mucosal protection
1. Prostaglandins - Misoprostol

2. Sucralfate and Bismuth Preparations

3. Antacids
Which class slows down peristalsis to cause less reflux (less stomach contents coming into the esophagus) and it also increases the strength of the esophageal sphincters
Prokinetic agent - Metoclopramide (Reglan®)
Classification: Antiulcer Agents slide
What is Histamine involved in
1. In allergy in mast cells

2. Gastric receptor H2

3. Regulation of sleep
Histamine slide
Histamine is synthesized in the Golgi apparatus of the mast cells and basophils by enzymatic __________ of histidine
decarboxylation
Histamine Biosynthesis slide
Treatment of allergic inflammatory disorders
H1
Treatment of gastric hypersecretory disorders
H2

Agents useful as anti-ulcers
Antagonists designed based on histamine structure with the Suffix 'tidine'
H2-Antihistamines or H2 blockers or H2RAs
H2-Antihistamines (H2RAs) slide
H2 Selectivity
Imidazole ring
Increases polarity and antagonistic binding
Flexible S chain
Antagonistic properties/activity
Guanidine
Increases activity
CN
SAR for H2-Antihistamines slide
Heterocycle - Selectivity

Chain - Binding

Guanidine - Properties/Activity

CN - Increase Activity
Which group is good for antagonistic activity and is very basic
Guanidine group
Which electronegative group (pulls electrons) decreases basicity of guanidine group to make it neutral leading to an increase in activity
Cyano (-CN) group
Cimetidine SAR slide
What part of the structure is associated with problems with Cimetidine
Imidazole ring
What are the issues with the Imidazole ring
1. Affects metabolism of several drugs by inhibiting major metabolism in liver CYP450

2. Potentiates toxicity of drugs with narrow therapeutic index
Problems with Cimetidine slide
Which is the least potent H2RA? The most potent?
Cimetidine is LEAST potent

Famotidine is MOST potent (30X more potent than cimetidine)
What is the potency of Nizatidine and Ranitidine
10X potent than cimetidine
What rings do Famotidine and Nizatidine have in place of the Cimetidine imidazole ring
Thiazole ring
Presence of ________ ring in Ranitidine accounts for much lesser DIs (~10%) as seen with Cimetidine
Furan ring
Modification of Cimetidine slide
First pass metabolism and 50% oral bioavailability
Cimetidine, Ranitidine and Famotidine
No significant first pass metabolism and 90% oral bioavailability
Nizatidine
Exercise: What is the significance of the following in H2-antihistamines?
Basic heterocycle = Help with selectivity for H2 receptor

Flexible chain = Binding

Polar neutral groups (Guanidine) = Antagonist Activity/properties
Presence of ___________ring in ranitidine accounts for much lesser DIs (~10%) as seen with Cimetidine

Imidazole
Thiazole
Isoxazole
Furan
Furan
Proton Pump Inhibitors (PPIs)
Omeprazole (Prilosec®)

Esomeprazole (Nexium®)

Lansoprazole (Prevacid®)

Dexlansoprazole (Dexilent®)

Pantoprazole (Protonix®)

Rabeprazole (Aciphex®)
How do PPIs work?
They block the proton pump in our stomach and decrease the concentration of HCl

Systemic (not ionized in normal plasma pH) -> Stomach Lining -> Ionized -> Covalent bonding with PP -> Trapped in stomach lining -> 24 hour effect
T/F PPIs are prodrugs
T
T/F PPIs are highly sensitive to acids which is not desired
T. Before absorption. readily converted into ionic (active) form under low pH (stomach): NOT DESIRED

Acid stable formulations are needed to allow absorption of drug in duodenum
What are the solutions to acid instability for PPIs
1. Enteric coated granules in capsules

2. Enteric coated tablets

3. Delayed release (dexlansoprazole)

4. Use basic conditions (eg with NaHCO3) - New drugs have sodium bicarbonate combination
Why are PPIs enteric coated granules, tablets and suspensions?
so that PPIs are not in direct contact with HCl

They are basic drugs so they can go into the intestine and be absorbed

Sometimes you will see there are new drugs now and we don't have the enteric coated granules and we have them as tablet
What PPI is a combination of omeprazole and sodium bicarbonate
Zegerid

Oral capsule OR Immediate Release Suspension and Chewable tablets
What is the purpose of sodium bicarbonate in Zegerid
1. Increase the pH of the stomach so that we don't have those low acidic conditions and Omeprazole will NOT be destabilized

2. Can also act as antacid
Can PPIs enter the CNS?
Yes bc they are Lipophilic
SE: HA (7%) and dizziness (2%)
PPIs overview slide
PPIs are commonly called
substituted benzimidazoles
PPIs require what 3 things for activation
1.Benzimidazole (red two rings)

2. Pyridine (one ring with N)

3. Sulfoxide (S=O)
S-enantiomer of omeprazole
Esomeprazole (Nexium)
Is the S-enantiomer of omeprazole superior to R-enantiomer in Potency and Pharmacokinetic profile?
S is not always superior to R. There are some controversy here
Dextro isomer of lansaprazole
Dexlansoprazol
PPIs: SAR Features slide
How does Omeprazole work
1. Acidic conditions (H+) in parietal cells (not stomach) activates PPIs when sulfoxide is converted to reactive cyclic sulfenamide

2. Sulfur in cyclic sulfenamide (activated PPI) reacts with cysteine sulfur of Proton pump (H+/K+-ATPase) to form disulfide bond

3. Proton pump inhibited irreversibly (covalent bond) - longer time to reverse effects of the drug
Steps of Omeprazole activation
Sulfoxide > reactive cyclic sulfenamie > PPI activated > reacts with cysteine Disulfide bond > Inhibit Irreversibly (covalent bond)
T/F PPI's have delayed onset and longer DOA
T
Why is there a longer time to reverse the effects of PPIs?
Because it is irreversible, we have to resynthesize new pumps because these pumps are non-functional, they won't go back to the original state

So even if you stop taking PPIs, you will still have the effect of the drug for 4-5 days because of that covalent bond
Is there a benefit of S omeprazole vs R
No
Is Omeprazole a prodrug?
We call them prodrug because they are not activated and we have a sulfoxide we call it chiral sulfoxide; chiral means two isomers
Where does Omeprazole get ionized?
Canalicular lumen with a pH of 0.8
Omeprazole slide
First in the blood, they are not ionized, the picture is the parietal cell that is in the stomach lining

The cytosol of the parietal cell ahs a pH of 7.1 almost neutral pH so they are NOT activated there

Once they enter this Canalicular lumen, which is the lumen that secretes the protons, it has the pumps, the pH of this lumen is 0.8, very acidic pH, 0.8; much lower than the stomach pH and because of that low pH the drugs gets ionized and they get concentrated because of ion trapping (they are trapped inside the cell), they get converted into the active form and they can inhibit the pump

So it gets activated and the S=O bond is broken and we have S—OH and it becomes ionized. This is good because it is at the active site, if this was in the stomach then the drug will be deactivated because they cannot inhibit the pump from the stomach, they have to enter the blood first then get to the site of action. So we get sulfuric acid

If you rearrange this, you form a cyclic form (cyclic sulfenamide) so sulfa again gets attached to the nitrogen here and we have a cyclic ring so we started with 3 cyclics and now we formed 4 cyclic forms and by doing that we lost the chirality of the drug and form the achiral, so now its achiral optically active. So whether you start with R or S isomer, you will only get one product which is not chiral, it is 4 cyclic ring. You only get one active drug which has free sulfur and the free sulfur can bind with the cysteine of the proton pump and form covalent bond (irreversible)

PPI's have delayed onset and longer DOA; it takes time to show effect because they can inhibit more than 90% of the pump, but it could be over a few days; and it is active for a longer time. Because it is irreversible, we have to resynthesize new pumps because these pumps are non-functional, they won't go back to the original state. So even if you stop taking PPIs, you will still have the effect of the drug for 4-5 days because of that covalent bond
At this stage we don't see any benefit of S omeprazole vs R
Remember this activation pathway
Omeprazole side effects
Abdominal pain

Flatulence

Diarrhea/Constipation

N/V
T/F Ion trapping in the secretory canaliculus of parietal cells account for good efficacy of PPIs
T
Proton Pump Inhibitors (PPIs) Omeprazole MOA
A cysteine residue of proton pump (H+/K+-ATPase) reacts with omeprazole to form covalent disulfide enzyme-inhibitor complex

Irreversible effect on secretion of gastric acid

Covalent binding with proton pump results in inactivation of the catalytic function of the proton pump
Proton Pump Inhibitors (PPIs) MOA slide
The red lines show how acid levels spike depending on the stimulus (food and drinks)

H2 blockers (blue line) you decrease the acidic level a little bit and it has better night time control since you are not eating anything at night; it's not as good as PPI

PPI: the green line, almost flat, once they reach the maximum effect, they can have very tight control on the acid secretion, but happens over time (4-5 days)

So PPI is our desired first line drugs
Omeprazole is metabolized mainly in the liver by
Sulfone, Hydroxylated and O-demethylated metabolites
Omeprazole has a Pharmacogenomic issues with
2C19 - interaction with Clopidogrel
Metabolism of Omeprazole slide
Interaction with clopidogrel? The drug may not be activated in pts taking omeprazole; don't worry about spacing it out (since omeprazole lasts long), it's best to avoid it completely.

However, clinically people still use it since it is not that bad in wild types, but for poor metabolizers the drug may not activated in pts taking clopidogrel, you may still see some use (if he's the pt. he'll go with pantoprazole or another PPI since they have lesser effect on the enzyme)
T/F Omeprazole and Esomeprazole are both generic OTC meds
T
What is the difference between Omeprazole and Esomeprazole
Omeprazole:
F= 40-65
Racemic mixture of R- and S-isomers (PO)

Esomeprazole:
F= >80
S-isomer of omeprazole (PO and IV)
Omeprazole and Esomeprazole will give rise to the same reactive species, _________ , which is achiral
Sulfenamide
T/ F There is no pharmacodynamic reason why the racemate or any of its enantiomers should differentially interact with the proton pump
T
T/F PK consequences of stereo-selective drug metabolism might anyway affect drug activity in vivo leading to improved efficacy and thus, better pharmacodynamics
F. According to Dr. Gupta increase dose similar efficacy
Omeprazole vs. Esomeprazole slide
T/F Dexlansoprazole is an isomer of lansoprazole
T
T/F Dexlansoprazole has a direct Pharmacodynamic advantage compared to Lansoprazole
F. All activated the same way
T/F Dexlansoprazole has a pharmacokinetic advantage compared to Lansoprazole
T. PK advantage due to DDR. DDR has advantage BUT Dex vs. Lans no advantage
T/F Dexlansoprazole is a Dual Delayed Release formulation
T. Two distinct drug release periods to prolong the plasma dexlansoprazole concentration-time profile and extend duration of acid suppression
T/F Dexlansoprazole produces a dual-peak PK profile that maintains therapeutic plasma drug concentrations longer than Lansoprazole and increases the percentage of time that intragastric pH >4
T. Lansoprazole has single-peak PK profile
T/F Dexlansoprazole is a prodrug
T. All PPIs are prodrugs
Why not DDR for lansoprazole
Make more money with new drug
Do you think Esomeprazole has better activity profile than Omeprazole in relation to forming covalent bonds with the receptor?
No. Bc of mechanism activation pathway Bc it form the Achiral carbon no matter which isomer we use
Do you think Dexlansoprazole has direct pharmacodynamic advantage over Lansoprazole?
No PD advantage

PK - Modified release form has advantage
Omeprazole is either available as such or its magnesium salt. Why not sodium or calcium or related salt?
It decreases chances of hypomagnesemia
Prokinetic Agents
Metoclopramide "The Mets have good kinetics"
Metoclopramide counter (opposes) factors leading to
esophagitis
What is Metoclopramide clinically used for
Useful in GERD and Acid reflux disease
What are the two MOA of Metoclopramide
1. Enhance peristalsis and gastric emptying: this means there will be less content in the stomach for a long time; eventually it will go into the intestine so less of the acid reflux disease

2. Also dopamine D2 antagonist: anti-nauseatic effect which can be correlated to the less content (since there is less content there is less nausea)
Metoclopramide enhances
Peristalsis and gastric emptying
T/F Metoclopramide enhances peristalsis and gastric emptying and is also a dopamine D2 antagonist for anti-nausea
T
Metoclopramide slide
Prostaglandins
Misoprostol
Misoprostol is a synthetic analogue of
PGE1
How does Misoprostol work
Antisecretory effect on gastric acid

Stimulates secretion of mucus & bicarbonate (cytoprotective)
T/F Misoprostol is a orally administered prodrug
T
What is the half life of Misoprostol
t1/2 <30min
Misoprostol is hydrolyzed to the pharmacologically active carboxylic acid derivative using
Esterases
Misoprostol slide
What makes up Sucralfate
1. Sulfuric acid ester

2. SUCROSE

3. ALUMINUM HYDROXIDE
Sucralfate MOA
Physical complex protects the ulcer from erosive action of pepsin and bile salts

***Physical barrier

Other mechanism:
Prostaglandin synthesis > secrete mucus
Sucralfate slide
Bismuth containing preparations
Colloidal bismuth subcitrate

Similar effects as sucralfate

Similar physical properties and coating effects
Bismuth subsalicylate
Pepto-Bismol®
T/F Bismuth subsalicylate is a salicylic acid and bismuth derivative
T.

Weak acid, strong base

Undergoes rapid dissociation within the stomach, allowing absorption of salicylate
Over _____% of the bismuth appears in the stool
99%

*Black stool and tongue not an issue
Bismuth subsalicylate is used as a
Anti-inflammatory and antacid

Anti-inflammatory because of the salicylic acid

Antacid because of the hydroxide; also as a coating because of this property to cover GI lining
T/F Bismuth subsalicylate gets absorbed and forms a physical barrier
F. Bismuth doesn't get absorbed

It does form that physical complex and once it is done, it is excreted in the stool
Bismuth subsalicylate slide
ANTACIDS
...
T/F Antacids are used for anti-ulcer effect
F. Antacids ↑ stomach pH: symptomatic relief, not anti-ulcer effects
Antacids are weak bases coupled with
polyvalent cations
Bicarbonates
1. Sodium Bicarb
2. Potassium Bicarb

NaHCO3, KHCO3
Carbonates
1. Magnesium Carbonate
2. Calcium Carbonate

MgCO3, CaCO3
Hydroxides
1. Magnesium Hydroxide
2. Aluminum Hydroxide

MgOH2 and AlOH3
Pt has Diarrhea, avoid
Mg
Pt has Constipation, avoid
Al, Ca
The bicarbonates release carbon dioxide which can cause
Belching and Metabolic Alkalosis
Pt has gas, use
1. Magnesium Hydroxide (MgOH2)
2. Aluminum Hydroxide (AlOH3)

Because bicarbonate will produce carbon dioxide and OH won't produce CO2
Pt is on sodium diet, avoid
Sodium bicarbonate
Antacids: MOA slide
Antacids may alter rate and extent of absorption of concomitantly administered drugs by altering
Ionization and Solubility
What are the 3 Antacids DDIs MOA
1. Neutralizing gastric pH (↓acidity, ↑pH)
Affects solubility

2. Chelation (polyvalent metal ions like Al3+, Mg2+)

3. Increasing urine pH (basic compounds)
Antacids: DDIs mech #1
Antacids: DDIs mech #2
Antacids: DDIs mech #3
Combination example
If you use combinations and on other meds then DI can be much worse bc have shorter and longer term effects

Advantages? Short and Long term effects

Disadvantages? DDI
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