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25 Cards in this Set

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GI System- Drugs for Peptic Ulcers by Maloney
GI System- Drugs for Peptic Ulcers by Maloney
What cells secrete gastric acid?

What is the body’s natural defense against gastric acid?

What stimulates HCI secretion by parietal cells?

What can you do to prevent HCI release from parietal cells?

What is the problem with using muscarinic blockers for the treatment of ulcers?
-parietal cells

-mucous and bicarbonate

-gastrin, histamine, ACh

-block histamine, block gastrin, block ACh, block H/K ATPase (proton pump)

-way too many side effects when you block ACh
What about mucus production/secretion?
parietal cell releases H+ which is about pH 2. The epithelial layer of cells which would typically be affected by this low pH is covered by a mucus layer which is pH 7. This mucus layer is produced by PGE2 (in the blood) via the EP3 receptor on the epithelial cell, which produces mucus and bicarb.
What other effect does PGs have on the stomach?
inhibit gastric acid secretion from parietal cells. so they generate the mucus layer in the stomach AND inhibit the production of gastric acid from the parietal cells. EP3 receptor activates Gi which inhibits cAMP, so you don't have activation of the proton pump. PGs also increase cell turnover and local blood flow
Main Causes of Peptic Ulcer Disease are:
Helicobacter pylori (main cause of ulcers)

NSAID-induced ulcer erosion potential (inhibit prostaglandins, which are protective of the stomach)

Increased acid (Zollinger-Ellison syndrome...tumor that produces a lot of gastrin, which means a lot of acid is produced)

Reduce gastric acid
Protect the mucosa from acid
Eradicate H. pylori
Recurrence without eradication – 80% in 1 year
Recurrence with eradication – less than 5% in 1 year
Gastroesophageal Reflux Disease (GERD) causes include acid reflux into the esophagus (which does not have much protection against acid). Treatment of GERD includes...
What doesn't work:
-increasing gastric mucus does not help since it's just for the stomach lining.
-eradicate H. Pylori is not an answer. it's only in ulcers, not GERD

What works:
reduce gastric acid production
tighten LES (surgery, not pharm)
increase gastric motility (lots of side effects, last resort, not talking about these)
neutralize gastric acid
Drug Classes Peptic Ulcer Disease and GERD
Proton pump inhibitors
H2 receptor antagonists
Prostaglandin analogs
Cytoprotective agents
Proton Pump Inhibitors Agents
Omeprazole (Prilosec, Zegerid)
Lansoprazole (Prevacid)
Rabeprazole (AcipHex)
Pantoprazole (Protonix)
Esomeprazole (Nexium)

*Acid labile Pro-drugs
*Administered as sustained release enteric coated preparations
*Except - Zegerid is immediate release omeprazole (has a coating on it which protects it from stomach acid, but when it gets to the alkaline intestine, the coating comes off and the omeprazole is absorbed)
Proton Pump Inhibitors Mechanisms
Inhibits H+-K+-ATPase that controls secretion of H+ from the parietal cell into the secretory canaliculi
PPI’s are weak bases
pKa of omeprazole is 4
What does that mean?
it's a charged drug at a certain pH. so it's circulating in blood (pH 7.4) so the drug is not charged. when it gets through the parietal cell and into the cannalicular space, the pH is really low, so the omeprazole is now protonated and charged. And it's this charged form that inhibits the proton pump.
Proton Pump Inhibitors: Mechanism of Action - Summary
The proton pump inhibitors are absorbed in the small intestine.

They are brought to the parietal cells via the systemic circulation.

They are activated in the acid environment of the gastric parietal cell secretory canaliculi.

The active metabolites bind covalently to the H+-K+-ATPase thereby irreversibly inhibiting acid release.

PPIs are usually taken 0.5-1 hour before meals. The don't work unless you have a lot of acid there already.
Proton Pump Inhibitors: Pharmacokinetics
Oral - all
Pantoprazole, lansoprazole, esomeprazole - IV
Plasma half life; 1-2 hours
Duration of action; 24-48 hours
Metabolized by cytochrome P450 system in liver

*irreversible inhibition of the proton pumps
Proton Pump Inhibitors: Clinical Use
Gastric and duodenal ulcers
-In combination with antibiotics for eradication of H. pylori
-Prevent/treat NSAID-induced ulcers (the BEST!)
-Zollinger-Ellison syndrome (Severe ulcers from a gastrin-secreting tumor) - Requires higher doses

Gastroesophageal reflux disease (GERD); work well
-Erosive esophagitis
Proton Pump Inhibitors Adverse Effects
Not a big deal:
Abdominal pain
Hyperplasia of gastric cells

Increased risk of pneumonia (when apsirated..kill microbes)
Increased risk hip fractures (bone has calcium. high pH doesn't absorb calcium as well)
PPI Drug Interactions
FDA – Avoid Co-administration of Clopidogrel and Omeprazole, Esomeprazole

Omeprazole inhibits the CYP2c19 which converts clopidogrel into the active metabolite.
Histamine H2-Receptor Antagonists Agents, and MoA, and clinical use
Cimetidine (Tagamet)
Ranitidine (Zantac)
Famotidine (Pepcid)
Nizatidine (Axid)

Reversible, competitive inhibitors of H2 receptors on the basolateral membrane of parietal cells

Gastroesophageal reflux disease
Gastric and duodenal ulcers
High doses for prevention of NSAID-induced ulcers

*don't work as well as PPIs
Histamine H2-Receptor Antagonists Adverse effects...and specifically Cimetidine
Diarrhea, Constipation, Headache, Drowsiness, Fatigue, Muscular pain

don't work as well as PPIs, but they've been around longer and they're cheaper. this is over the counter stuff.

cimetidine inhibits androgen receptors also. so you get gynecomastia in men and galactorrhea in the ladies.

it's also a big inhibitor of CYP450: Alter the metabolism and increase the levels of drugs that are substrates for the cytochrome P450 system
Prostaglandin Analogs Agents, MoA
Misoprostol (Cytotec)
-Synthetic analog of prostaglandin E1
-binds to EP3 receptor on EPITHELIAL cells, which increases the mucus and bicarb production. if it binds to the EP3 receptor on the PARIETAL cell, you're going to prevent the histamine from stimulating the proton pump, and decrease the activity of the proton pump (this is a bigger effect)
Misoprostol MoA summary
Activates prostaglandin receptors (EP3) on epithelial cells thereby increasing mucous and bicarbonate secretion.

Activates prostaglandin receptors (EP3) on parietal cells. This activates Gi, which inhibits the production of adenylyl cyclase thereby decreasing the activity of the proton pump and decreasing acid secretion.
What main group of drugs inhibits prostaglandin formation?

What enzyme do they inhibit that is involved in prostaglandin synthesis in the gut?

- COX-1
What is the main clinical use of misoprostal? Adverse effects? contraindications
Use: Prevention of mucosal injury caused by NSAIDs

AE: Diarrhea with or without abdominal pain
-Up to 30% of patients (that's huge)
-Seen about 2 weeks after starting therapy and resolves spontaneously in about 1 week

Inflammatory bowel disease--> Exacerbation
Pregnancy--> Cause abortion by increasing uterine contractility
Cytoprotective Agents
Sucralfate (Carafate)
-Complex of sulfated sucrose and aluminum hydroxide

take the sucralfate, and in the stomach it forms a gel which is negatively charged. it's attracted to the positive charges of the ulcer and covers it up. so you don't have acid and pepsid attacking the ulcer anymore.

At low pH (<4) it cross-links and forms a gel-like substance that adheres to epithelial cells and ulcers
Lasts for as long as 6 hours
This protects ulcerated tissue from acid, pepsin and bile salts

don't take an antacid before taking this sucralfate because you need the low pH for it to form the gel.
Sucralfate (Carafate) clinical use:
duadenal and gastric ulcers. take 1 gm four times a day on an empty stomach, one hour before each meal and at bedtime.

AE: constipation (bc of the aluminum)
Bismuth Subsalicylate (Pepto-Bismol), MoA, clinical use.
Crystalline complex of trivalent bismuth and salicylate suspended in a mixture of magnesium aluminum silicate clay

Binds to mucosal glycoproteins
Coats the crater
Binds pepsin
Direct antimicrobial activity against H pylori

Clinical Use:
Gastric and duodenal ulcers
In combination with antibiotics for eradication of H. pylori

Adverse: darken stool and tongue (from bismuth sulfide)
Antibiotics: tx of H Pylori
Triple therapy: 2 abx and a PPI
Amoxicillin or metronidazole, Clarithromycin

Quadruple therapy: 2abx, PPI, bismuth
Tetracycline, Metronidazole
Bismuth subsalicylate

Sequential therapy:
PPI plus amoxicillin for five days
Then PPI plus clarithromycin plus tinidazole for another five days.