Acid Peptic Diseases

What does swallowing trigger?

Relaxation of the lower esophageal sphincter (LES)

Allows passage of food from the esophagus to the stomach

What does contraction of the LES do?

Maintains a high pressure gradient above the esophagus to prevent the back flow of stomach contents

What does food stimulate in the stomach?

Production of acid, pepsinogen, and mucus

What does the low pH of the stomach do?

Denature/unfolds proteins

Converts pepsinogen to pepsin

Define pepsin

Protease that cleaves proteins into polypeptides with pH optimum 1.5-2.5

What does the antrum of the stomach secrete?

Mucus, pepsinogen, and gastrin

What does the body of the stomach secrete?

Mucus, pepsinogen, and HCl

Where does chyme pass through?

The pyloric sphincter

How does carbonic anhydrase produce H+ for stomach acid?

CA takes CO2 and water to make H2CO3

H2CO3 gives off an H+, leaving you with HCO3-

HCO3- diffuses by active transport into the blood

How does H+/K+ ATPase work?

An antiporter that moves protons into the lumen and brings potassium into the cell

How is gastric acid formed in the lumen?

Through diffusion, Cl- will also diffuse out into the lumen

The H+ and Cl- then create HCl

What does histamine do?

Stimulates H2-receptors on parietal cells

Increases cAMP and PKA

Triggers the activation of H+/K+ ATPases

What does gastrin do?

Binds gastrin/CCK-B receptors

Can stimulate histamine to be released from an ECL cell through this receptor

What does acetylcholine do?

Stimulates muscarinic M3-receptors (M3R)

What stops the release of gastrin?

When the lumen reaches a certain pH, it will tell D cells to release somatostatin which binds to G cells, telling them to stop releasing gastrin

How does histamine, gastrin, or Ach affect the canalicular membrane?

Stimulate rearrangement of the canalicular membrane to allow H/K-ATPases located in the tubulovesicles to fuse with/be inserted into the membrane

What do surface mucous cells secrete?

Mucus, trefoil peptide, bicarbonate secretion

Help to protect other cells of the stomach from stomach acid

What do parietal cells secrete?

Acid and intrinsic factor

What do ECL cells secrete?

Histamine

What do chief cells secrete?

Pepsinogen

What are physical barriers that protect the GI tract from acid?

LES and pyloric sphincter

How does the mucus layer protect epithelial cells from acid?

By trapping HCO3-

pH = 7

What do prostaglandins do?

Stimulate mucus production, increasing protective barrier

Stimulate HCO3- secretion into mucus

Inhibit acid secretion by parietal cells

Increase blood flow to mucosa and walls of GI tract

Define acid peptic diseases

Irritation, erosion, or ulceration of the mucosal lining of parts of the upper GI tract from acid

Where does GERD occur?

Esophagus

Where does PUD occur?

Duodenum and stomach

Usually affects areas more distal to the stomach

Define erosion

More superficial

Affects the mucosa

Define acute ulceration

Deeper damage than erosion

Affects the submucosa

Define chronic ulceration

Affects the ability to move food down into the esophagus

Affects smooth muscle (muscular propria)

Define GERD

Gastroesophageal Reflux Disease

Retrograde flow of gastric acid and stomach contents into the esophagus

What are underlying anatomical causes of GERD?

Decreased LES tone = spontaneous TLESRs

Delayed gastric emptying

Increased gastric pressure

Hiatal hernia

Impaired esophageal peristalsis

Impaired mucosal defense

What are complications of GERD?

Esophagitis, erosive esophagitis, esophageal strictures, Barrett's esophagus

Define esophagitis

Acute inflammation of superficial layers of esophageal mucosa

Define erosive esophagitis

Chronic inflammation that leads to erosion of the esophageal epithelium into the submucosal and muscular layers

May result in ulcers and bleeding

Define esophageal strictures

Narrowing of distal esophagus due to chronic inflammation/formation of fibrous scar tissue

Define Barrett's esophagus

Replacement of squamous epithelial lining by specialized columnar type epithelia

Increased prevalence of strictures

Increased risk of esophageal adenocarcinoma

What are examples of proton pump inhibitors (PPIs)?

Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole

What is the mechanism of action of PPIs?

Covalent inhibition of parietal cell H+/K+ ATPase-mediated secretion of acid into stomach lumen

Body will have to make a new ATPase in order to regain function

Direct effect on acid secretion

What are key structures of PPIs?

Benzimidazole, sulfoxide/sulfinyl, pyridine

What activates PPIs?

PPIs are prodrugs that are activated by acid to form irreversible disulfide bonds with a cysteine amino acid of the H+/K+ ATPase

What metabolizes omeprazole?

CYP3A4 and CYP2C19

High metabolism, many DDIs w/ 2C19 substrates

How can omeprazole be metabolized?

Demethylation, sulfonylation, or hydroxylation

How can lansoprazole be metabolized?

Hydroxylation or sulfonylation

How can pantoprazole and rabeprazole be metabolized?

Sulfonylation or demethylation

Describe the absorption of PPIs

Prodrugs activated at low pH

Enterically-coated to prevent activation in stomach

Describe the metabolism of PPIs

CYP3A4 substrate (all undergo sulfonylation)

CYP2C19 substrate (demethylation or hydroxylation)

CYP2C19 inhibitor (esomeprazole, omeprazole)

Describe DDIs of PPIs

Increase gastric pH, thus impacting ADME of drugs requiring acidic pH (phenytoin, mesalamine, fluoroquinolone)

Clopidogrel-activated by CYP2C19

What are examples of H2-Receptor Antagonists (H2RAs)?

Cimetidine, famotidine, nizatidine, ranitidine (discontinued in 2020)

What is the mechanism of action of H2RAs?

Reversible inhibition of H2 receptor by mimicking interactions with histamine

Indirect effect on acid secretion by reducing H+/K+ ATPase insertion into canalicular membrane

How does histamine interact with H2 receptors?

Through hydrogen bonding and ionic interactions

What key features allow H2RAs to mimic histamine interactions?

Heterocycle, thioether, guanidine

Compare the effectiveness at decreasing acid levels of PPIs to H2RAs

PPIs decrease acid levels at meals and at night

H2RAs are most effective at decreasing acid levels at night

H2RAs are less effective at decreasing acid levels at night

What is a major consequence of cimetidine?

Strong CYP inhibitor = impaired CYP metabolism of other drugs

Inhibits CYP3A4, CYP2C9, CYP2D6, and CYP1A2

How is cimetidine metabolized?

Weak CYP substrate

Sulfoxidation or hydroxylation

How is nizatidine metabolized?

Demethylation, N-oxidation, sulfoxidation

How is famotidine metabolized?

Sulfoxidation

Describe the absorption of H2RAs

OCT2 substrate (cimetidine)

Describe the metabolism of H2RAs

Cimetidine CYP weak substrate and strong inhibitor (3A4, 2C9, 2D6)

Describe the excretion of H2RAs

Adjust dose if renal impairment

Describe DDIs of H2RAs

Increases gastric pH, thus impacting ADME of drugs requiring acidic pH (ketoconazole, iron salts)

What are examples of antacids?

Al(OH)3, Mg(OH)2, CaCO3, and NaHCO3

What is the mechanism of action of antacids?

Weak bases that neutralize stomach acid

No impact on acid secretion

What are benefits of antacids?

Rapid acting, short duration of action

What are side effects of antacids?

Metabolic alkalosis and belching (Ca2+, Na+)

Hypercalcemia (Ca2+)

Caution with renal insufficiency (Al2+, Mg2+, Ca2+)

Describe DDIs of antacids

Increases gastric pH, thus impacting ADME of drugs requiring acidic pH

Define PUD

Peptic Ulcer Disease

Formation of gastric or duodenal ulcers due to breakdown of the mucosal defenses

What are underlying causes of PUD?

H. pylori, NSAIDs, stress-induced mucosa damage/critical illness

How does H. pylori cause PUD?

Urease neutralizes acidic environment

Catalase evades ROS in phagocytes

Additional enzymes break down mucus and promote colonization in gastric mucosa

How do NSAIDs cause PUD?

Inhibit mucosa prostaglandin biosynthesis, decrease mucous and HCO3- production

What are complications of PUD?

Bleeding, cancer

What are examples of mucosal protectants?

Sucralfates, bismuth subsalicylate, misoprostol

What is the mechanism of action of sucralfate?

At pH < 4, polymerizes to a paste

Binds proteins in ulcer, protecting against acid (chemical protection)

What is the mechanism of action of bismuth subsalicylate?

Binds ulcers/erosions, providing physical protection against acid

Salicylate reduces inflammation

What is the mechanism of action of misoprostol?

Synthetic prostaglandin E1 analogue that replaces prostaglandin stores depleted by NSAIDs

Promotes mucosa defense through bicarbonate and mucus production

When is misoprostil contraindicated?

In pregnancy - stimulates uterine contractions

What are examples of antibiotics that target H. pylori?

Metronidazole, clarithromycin, amoxicillin, tetracycline, levofloxacin

What is the class and MOA of tetracycline?

Class: tetracycline

MOA: inhibits protein synthesis (30S)

What is the class and MOA of clarithromycin?

Class: macrolide

MOA: inhibits protein synthesis (50S)

What is the class and MOA of amoxicillin?

Class: penicillin

MOA: inhibits cell wall synthesis

What is the class and MOA of levofloxacin?

Class: fluoroquinolone

MOA: inhibits nucleic acid synthesis

What is the class and MOA of metronidazole?

Class: nitroimidazole

MOA: inhibits nucleic acid synthesis