GI Pharmacology 1- Khan

Name of 3 mediators used in gastric acid secretion:

Name of 3 mediators used in gastric acid secretion:

1. gastrin

2. histamine

3. ACh

What cell type is involved in GI secretion?

parietal cells

Where is ACh released from?

vagus nerve terminal

What histamine receptor subtype is present in the parietal cells?

H2 receptors

Discuss the entire signal transduction following H2 receptor activation:

1. histamine binds to H2 receptor

2. H2 receptor activates AC

3. AC converts ATP to cAMP

4. cAMP activates PKA

5. PKA causes vesicle containing H+/K+ ATPase to move to surface of parietal cell

Following the fusion of the vesicles with the apical membrane, how is the proton released?

• active transport!

  • K+ moves into the cell, H+ move out of the cell

  • needs ATP to do this

What is the role of the apical membrane K channel?

how acid gets into the stomach?

What is the role of mucin against GI acidity?

an insoluble gel that coats the mucosal surface and protects

What is the role of somatostatin against acidity? Include it’s direct effect.

somatostatin DIRECTLY inhibits parietal cell gastric secretion

What is the role of PGs against acidity?

inhibits acid secretion by increasing bicarb secretion and increases mucus production

Answer the following about SUCRALFATE:

• How is it activated?

• How does it work as a coating agent?

• What, if any, effect does it have on gastric pH?

• Does it cause constipation or diarrhea?

• activation- in acidic pH undergoes cross-linking and polymerization to form a VISCOUS GEL

• works to protect from pepsin and acid

• NO EFFECT ON GASTRIC pH

• causes CONSTIPATION

Answer the following about Bismuth Subsalicylate:

• What does the drug do in the stomach?

• What are its antimicrobial effects?

• What are the ADRs?

• What is the BBW?

• undergoes DISSOCIATION in the stomach

• DIRECT antimicrobial effect against H.PYLORI

• ADRs- BLACKENING of stool, DARKENING of tongue, TINNITUS

  • (think Bismuth= black)

• BBW- REYE’s SYNDROME associated w/ salicylate in kids/teens

Answer the following about MISOPROSTAL:

• What type of derivative is it?

• What is its indication?

• What is the BBW?

• synthetic PG E1 derivative

• indicated in NSAID INDUCED ULCERS ONLY

• BBW- ABORTION (can cause uterine contractions)

What are the names of the agents that neutralize acids? (brand/generic)

• Antacids

  • Aluminum Hydroxide+Mg+simethicone (Maalox)

  • Magnesium Hydroxide (milk of magnesia)

  • Calcium Carbonate (Tums)

  • Sodium Bicarbonate/aspirin/citric acid (ALKA-SELTZER)

• Alginic Acid

Answer the following about ANTACIDS:

• What is their effect on gastric acidity, pH, and pepsin inactivation?

• They can cause acid _________.

• What is the reason for their drug interactions?

• neutralize acid, increase gastric pH, inactivate pepsin

• they can cause acid REBOUND

• reasons for DI- can affect absorption of other drugs by binding to the drug OR altering the pH

  • ex: some drugs need acidic environment to be absorbed

What is acid rebound? Which antacids cause high acid rebound? Which cause low acid rebound?

acid rebound- persistent acid secretion even though pH is normal

low acid rebound- Al and Mg (Maalox, milk of magnesia)

high acid rebound- NaHCO3 (sodium bicarb) and CaCO3 (calcium carb) (Tums, Alka-Seltzer)

What are the ADRs of calcium carbonate, magnesium, and aluminum?

calcium carbonate- belching, hypercalcemia, constipation

magnesium- diarrhea

aluminum- constipation

What 2 drug classes suppress acid secretion?

• H2 blockers

• PPIs

What are the names of the H2 blockers? (brand/generic)

• Cimetidine (Tagamet)

• Ranitidine (Zantac)

• Nizatidine

• Famotidine (Pepcid)

Answer the following about Cimetidine:

• What is the role of the CH3 group in imidazole ring?

• What is the role of the 4 atom linker?

• What is the S role in potency?

• Where does hydroxylation take place in the molecule?

• What is the problem with the imidazole ring?

• What are the endocrine ADRs?

• What are the effects of the endocrine ADRS?

• role of CH3- H2 SELECTIVITY

• role of 4 atom linker- extends guanidine group into antagonist binding region

• S role- has higher potency then C or O

• Hydroxylation occurs on the CH3 GROUP OF THE IMIDAZOLE RING

• Problem with the ring? DRUG INTERACTIONS! Inhibit CYP450 enzymes

• endocrine ADRs-

  • inhibit binding of DHT to androgen receptor

  • inhibits estrogen metabolism

  • increases prolactin levels

• effect of endocrine ADRs- gynecomastia and impotence in men

What group does Cimetidine have that NO OTHER H2 blocker has?

IMIDAZOLE RING

Answer the following about Ranitidine:

• The imidazole is replaced with a furan. What is the advantage?

• What happens when the S of 4-atom linker is replaced by O?

• advantage- less/no drug interactions

• less activity

Answer the following about all H2 BLOCKERS (Cimetidine, Ranitidine, Nizatidine, Famotidine:

• MOA of H2 blockers

• ADRs of H2 blockers

• Why is fluconazole/itraconazole absorption reduced when taken with H2 blockers?

• MOA- COMPETITIVE H2 RECEPTOR ANTAGONIST

• ADRS- confusion and vit b12 deficiency

• Can’t be taken bc they need an acidic gut for absorption and H2 blockers inhibit the acid

What are the names of the PPIs? (brand/generic)

• Omeprazole (Prilosec)

• Lansoprazole (Prevacid)

• Dexlansoprazole

• Pantaoprazole (Protonix)

• Esomeprazole (Nexium)

What is the structure of benzimidazole?

Given the structure, be able to identify where omeprazole is protonated in acidic pH?

• Drug is protonated on the “N” of benzimidazole

What is the MOA of PPI?

• “proton pump inhibitor” DUH

  • basically: Sulfenamide reacts with Cys residue H+/K+ ATPase, forms disulfide linkage (covalent bond) and irreversibly inactivates the enzyme

If PPI’s are prodrugs, how do they reach parietal cells? What is the drug converted into?

• enteric coated tablets

• once in intestine, coating is dissolved and drug is absorbed and diffuses to parietal cells

• then converted into SULFENAMIDE

Answer the following about PPIs (-prazoles):

• What enzymes are involved in metabolism?

• What are the drug interactions?

• What is the specific drug reaction with clopidogrel?

• What are the complications with long term use?

• What are the ADRs

• enzymes: CYP2C19, CYP3A4

• DI: inhibit CYP2C19 (increase warfarin/phenytoin), increase GI pH (-azoles, iron)

• CLOPIDOGREL+ PPI (esomeprazole/omeprazole)= DECREASED CLOPIDOGREL EFFECT

• long term complications: osteoporosis, hypomagnesemia, vit B12 deficiency

• ADRs- acute interstitial nephritis, increase risk of C.difficile associated diarrhea, increase risk of pneumonia in hospitalized pts.

What are the 3 main causes of PUD?

1. H. pylori bacteria

2. chronic NSAID use

3. Stress

How does H. pylori survive in an acidic environment?

• by increasing pH

  • produces urease which converts urea to ammonia

  • ammonia buffers H+

What is the role of H.pylori in PUD?

overall effect: increase gastrin = increase parietal cell proliferation and acid secretion= PUD

What systemic effects are produced by NSAIDs?

• inhibit COX= decrease PGs

  • increase gastric acid secretion

  • decrease bicarb/mucus production

  • decrease blood flow

• mucosal damage

What topical effects are produced by NSAIDs?

• cell damage

  • NSAID enters cells in non-ionized form and in cytoplasm becomes trapped and ionized= cell damage

What mechanisms do the following antibacterial drugs eliminate bacteria?

• Amoxicillin

• Tetracycline

• Clarithromycin

• Metronidazole

• Amoxicillin—> inhibit bacterial cell wall synthesis

• Tetracycline and Clarithromycin—> inhibit bacterial protein synthesis

• Metronidazole—> damage bacteria DNA

What are the tx options for GERD?

• antacids

• PPIs

• H2 blockers

• metoclopramide

What is a prokinetic drug?

drug that increases MOTILITY/movement

What is the dopaminergic mechanism of metoclopramide?

• DOPAMINE ANTAGONIST!!!!!!!!!!

  • Dopamine D2 receptor antagonist (central and peripheral)

  • Central dopamine antagonism—> anti-nausea effect

  • Dopamine antagonism in the GIT—> increase prokinetic effect

    • Dopamine decrease motility in GIT

What are the ADRs of metoclopramide? What is the BW?

ADRs- drowsiness, restlessness, dystonic reactions

BBW- tardive dyskinesia