Gastrointestinal Pharmacology

Question 1

What are the two causes of peptic ulcers? – Aggressive factors that contriubute to their developpment?

What are the body’s defense mechanisms against the development of peptic ulcers?

Answer 1

• Causes
  
  • Helicobacter pylori
  • Long term use of NSAIDs (indomethacin and ibuprofen)
• Aggressive factors
  
  • gastric acid & smoking (nicotine stimulates gastric acid)
• Defense mechanisms
  
  • mucus
  • bicarbonate
  • blood flow
  • prostaglandins

Question 2

Describe the control of gastric acid secretion.

Answer 2

• When parasympathetic nervous system is activated (drink food/caffeine)
  
  • increases gastrin level – stimulates ECL cells to
    
    • release histamine – stimulates H2 receptor on parietal cells
      
      • increases intracellular cAMP level
        
        • increases activity of proton/K⁺ ATP pump,
          
          • which increases gastric acid (HCl) secretion
  • increases release of ACh, which acts on M3 receptor on parietal cells
    
    • increases intracellular Ca²⁺ level, which increases activity of proton/K⁺ ATP pump
      
      • which increases gastric acid (HCl) secretion

Question 3

What are the 4 classes of drugs that can decrease gastic acidity?

Answer 3

1. H⁺/K⁺- ATPase inhibitors
2. H₂ blockers
3. Antacids (weak bases)
4. Anticholinergics (not common b/c systemic adverse effects)

Question 4

What are the PPIs & what is their mechanism of action?

Answer 4

• Drugs
  
  • omeprazole (prilosec, rapine, zegerid)
  • Lansoprazole (prevacid)

protom pump inhibitors

• react with H⁺/K⁺ ATPase to irreversibly inactivate the enzyme
  
  • lasts lifetime of the pump, so long-lasting
• inhibit both fastign and meal stimulated secretion

Question 5

Pharmacokinetics of PPIs?

Answer 5

• Prodrugs
  
  • orally administered, absorbed in intestin & activated in parietal cells
  • slow onset of action
  • bioavailability is decreased by food
    
    • except dexlansoprazole
  • Rapid first-pass hepatic metabolism
    
    • CYP2C19
    • CYP3A4

Question 6

Clinical uses of PPIs?

Answer 6

• Peptic ulcer disease: first-line drugs & most widely used
• sever symptomatic GERD
• nonulcer dyspepsia
• Prevention of stress-related mucosal bleeding
• gastric acid hypersecretion: gastrinoma
• Prevent NSAIDS-induced GI side effects
  
  • ie. patients with arthritis

Question 7

Adverse effects of PPIs?

Answer 7

• well tolerated & relatively safe
  
  • nausea, diarrhea, abdominal pain
• Long-term use
  
  • increase Clostridioides difficle-associated diarrhea
    
    • b/c increased gastric pH
  • may reduce plasma Vitamin B12, non-heme iorn, Ca²⁺, Mg²⁺ levels
    
    • b/c the reduced release of these components from food due to the increased gastic pH

Question 8

drug-drug interaction PPIs?

Answer 8

• drugs that the bioavailability is affected by intragastric acidity
  
  • itraconazole
  • digoxin
• Esomerprazole and omeprazole: CYP2C19 inhibitors
  
  • interact with
    
    • phenytoin
    • diazepam
    • theophyline
    • clopidogrel
  • dosage adjustment

Question 9

What are the H₂ Histamine receptor antagonists and what is their mechanism of action?

Answer 9

• Drugs
  
  • Cimetidine (tagamet)
  • Famotidine (pepcid)
  • ranitidine (Zantac)
• mechanism of Action
  
  • competitively and selectively bind to H₂ receptors, therefore reduce histamine-induced acid
  • therefore, do not COMPLETELY block gastric acid secretion

Question 10

Clinical uses H₂ receptor antagonists?

Answer 10

• Peptic ulcer disease: first-line drugs & most widely used
• sever symptomatic GERD
• nonulcer dyspepsia
• Prevention of stress-related mucosal bleeding
• gastric acid hypersecretion: gastrinoma
• Prevent NSAIDS-induced GI side effects
• ie. patients with arthritis

Question 11

Adverse effects H₂ receptor antagonist?

Answer 11

• extremely safe. Tolerance develops
  
  • cimetidine: ginds to dihydrotestosterone receptors – exaggerated estrogen effects

Question 12

Drug-drug interaction of H₂ receptor antagonists?

Answer 12

• interact with drugs metabolized by
  
  • CYP1A2
  • CYP2D6 and/or
  • CYP3A4 (azole antifungal agents)
• affect inhibit first-pass metabolism of ethanol
  
  • except famotidine

Question 13

What is the mechanism of action of antacids?

Answer 13

• neutralize gastric acid
• Mg²⁺, Al³⁺, Na⁺, and Ca²⁺ salts are the most common
• very rapid, but short duration of action

Question 14

clinical uses of antacids?

Answer 14

short-term relief of symptoms, used as-needed basis

Question 15

adverse effects of antacids?

Answer 15

• constipation (aluminum)
• diarrhea (magnesium)
• altered electrolyte balance
• if you combine both calcium & magnesium can reduce both constipation & diarrhea

Question 16

drug-drug interactions of antacids?

Answer 16

• affects absorption of some antibiotics
  
  • tetracyclines & fluroquinolones
  • separate administration time by several hours

Question 17

Antibiotics used to cur H. pylori infection-induced peptic ulcer

Answer 17

• First line
  
  • clarithromycin
  • amoxicillin
  • tetracycline
• second line
  
  • Metronidazole
    
    • if allergic to penicillin
  • Refabutin
    
    • if clarithromycin or metronidazole resistance

Question 18

What is the drug name & mechanism of action for colloidal bismuth compounds?

Answer 18

• name
  
  • bismuth subsalicylate (pepto-bismol)
• mechanism of action
  
  • coat ulcer and erosions
  • stimulate the secretion of prostaglandin, mucus, and bicarbonate
  • antimicrobial effects: bind to bacteria and enterotoxins
  • reduced stool frequencey and liquidity

Question 19

Clinical uses of Bismuth compounds?

Answer 19

• nonprescription: treat dyspepsia dn prevent traveler’s diarrhea
• combined with PPI and antibiotics: H. pylori infection-caused peptic ulcer

Question 20

Adverse effects & contraindications for bismuth compounds?

Answer 20

• adverse effects
  
  • black tongue and stool
• contraindication
  
  • renal insufficiency and allergies to salicylates

Question 21

Sucralfate mechanism of action?

Answer 21

• pepsin inhibitor
• activated by acid – treating w/ antacid will decrease efficiency
• Mechanism of action (protect mucosa)
  
  • physical barrier
  • inhibit pepsin mediated hydrolysis of mucosal protein
  • stimulates mucosal prostaglandin and bicarbonate secretion

Question 22

Clinical uses of sucralfate?

Answer 22

• prophylaxis of stress gastritis
• peptic ulcer
• ulcers not caused by acid: oral mucositits and bile reflux gastropathy

Question 23

Adverse effects & drug-drug interactions of sucralfate?

Answer 23

• adverse effects
  
  • may develop constipation due to the aluminum salt
• drug-drug interaction
  
  • may reduce the absorption of some oral medications
  • time-lapse is important

Question 24

Draw this

Question 25

What is the 3 step treatmetn strategy for H. pylori peptic ulcer? Provide example of the triple therapy. Provide example of quadruple therapy.

Answer 25

1. elimate the bacteria (antibiotics) 2. reduce stomach acid (protom pump inhibitor) 3. protect the mucus membrane (bismuth subsalicylate) * Triple therapy * PPI-CA: PPI + clarithromycin + amoxicillin * PPI-CM: PPI + clarithromycin + metronidazole * penicillin allergy * PPI + amoxicillin + rifabutin * clarithromycin or metronidazole resistance * Quadruple therapy * Bismuth-based quadruple therapy * bismuth subsalicylate + mtronidazole + tetracycline + a PPI * Clarithromycin-based quadruple therapy * amoxicillin + clarithromycin + metronidazole + a PPI

Question 26

What are the therapeutic strategies to treating inflammaoryt bowel disease? What are the two common inflammatory bowel diseases?

Answer 26

* Therapeutic strategies * inhibit the inflammatory responses * suppress immune responses * Inflammatory boewl disease 1. Ulcerative colitis (UC) 2. Crohn's disease (CD)

Question 27

What is the inflammatory supressor? What is it ised to treat?

Answer 27

Inflammatory bowel * 5-Aminosalicylates (5-ASA, mesalamine: * Sulfasalazine: 5-ASA-AZO bond-sulfapyridine * sulfapyridine can be absorband & causing adverse effects * Olsalazine: 5-ASA-AZO bond-5-ASA * Balsalazie: 5-ASA-AZO bound-inert compound

Question 28

5-ASA mechanism of action?

Answer 28

* not fully understood * Thought to inhibit the following: * IL-1 and TNF-alpha expression * lipoxygenase pathway * NG-kB * reactive oxygen species

Question 29

Clinical uses of 5-Aminosalicylates?

Answer 29

* induce and maintain remissionof mild or moderate ulcerative colitis (inflammatory bowel disease) * Rheumatoid arthritis (sulfasalazine)

Question 30

Adverse effects & drug-drug interactions of 5-Aminosalicylates?

Answer 30

* Adverse Effects * sulfasalazine * more adverse effects * others: well tolerated * dyspepsia (indegestion) * skin rash * headache * abdominal pain * rare but serious: nephrotoxicity * Drug-drug interactions * fomulations with pH sensitive enteric coatings shouldn ot be co-administerd with anti-acids * if co-administered with anti-acid drugs, they will not make it to the intestines

Question 31

What the glucocorticoid/corticosteroids? What are they used to treat?

Answer 31

Used to treat inflammtory bowel disease * prednisone and prednisolone: oral * Budesonide * oral * synthetic analogue of prednisolone * extensive first-pass metabolism by CYP3A4 -- low bioavailability -- les change to cause systemic adverse effects * Hydrocortisone: enemas, foam or suppositories

Question 32

Glucocorticoid/corticosteroids mechanism of action?

Answer 32

* Overview * produced by adrenal glands * only free form will enter into the cells * bind to specific receptors * will dimerize into the nucleus * bind to glucocorticoid response element in the gene * effect gene expression & protein expression * alter cellular function * MOA * inhibit expression inflammatory mediators * increase expression of antiinflammatory mediators

Question 33

Clincal uses of glucocorticoid/corticosteroids?

Answer 33

* Budesonide * induce remission in mild adn moderate IBD * Prednisone and prednisolone * induce remission and control acute moderate to severe active IBD * more potent than 5-ASAs

Question 34

Adverse effects and drug-drug interactions with glucocorticoid/corticosteroids?

Answer 34

* Adverse Effects * prolonged use (except budesonide) can cause lots of adverse effects adn the drugs have to be tapered gradually when discontinuing * mood changes, fluid retention, increased appetite and glucose level * increase chances of infection, peptic ulcers, osteoporosis, glaucoma, and cataract * High dose: * hypothalamic-pituitaty-adrenal axis suppression * temorarily show growth rate in children * Drug-drug ineractions * budesonide interacts wtih CYP3A4