Upper GI Pharmacology

Question 1

Antibiotics role in peptic ulcers

Answer 1

• critical role in eradicating H. pylori infection (associated w/many ulcers)
• use: reduce rate of recurrence of gastric and duodenal ulcers
• one component of “triple” or “quadruple” therapy

Question 2

Triple therapy drugs/use

Answer 2

• use: tx of H. pylori-associated ulcers
• PPI
• Clarithromycin
• Amoxicilin
• OR Metronidazole

Question 3

Quadruple therapy drugs

Answer 3

• Bismuth subsalicylate
• Metronidazole
• Tetracycline
• PPI or H2 antagonist

Question 4

Sequentioal therapy drugs

Answer 4

• Amoxicillin + PPI (5 days)
• then Clarithromycin + Tinidazole + PPI (5 days)

Question 5

Proton Pump Inhibitors: MOA

Answer 5

• administered as prodrug ==> systemic circulation ==> parietal cells ==> active sulfenamide
• covalent linkage to H⁺-K⁺-ATPase irreversible inactivates enzymes
  
  • 18 hours req. for synthesis of new enzyme

Question 6

Examples of PPIs

Answer 6

• Omeprazole (Prilosec)
• Lansoprazole (Prevacid)

Question 7

Clinical uses of PPIs

Answer 7

• GERD
• Peptic Ulcer Disease
• NSAID-induced ulcers
• Zollinger-Ellison syndrome (symptom relief/ulcer healing)

Question 8

H₂ Receptor Antagonists examples

Answer 8

• Ranitidine [Zantac]
• Cimetidine [Tagamet]
• Famotidine [Pepcid]
• Nizatidine [Axid]

Question 9

H₂ Receptor Antagonist: MOA

Answer 9

• reversible, competitive block at parietal cell H2 receptors on basolateral membrane
  
  • better @ blocking nocturnal acid secretion (H₂-mediated) vs. meal-stimulated (ACh/gastrin)
• Less efficacious than PPIs but still suppress 24 hour acid secretion by 70%.

Question 10

PPIs: Pharmacokinetics/Dosing

Answer 10

• rapidly absorbed
• good oral availabilty w/enteric coating
• dosing: empty stomach 1 hour before meals
• metabolism: CYP450

Question 11

H₂ Antagonists: Pharmacokinetics/Dosing

Answer 11

• rapidly absorbed from GI tract
  
  • some enhancement w/food
• dosing: BID
• metabolism: mostly renal ==> dosage adjustment w/impaired renal fxn

Question 12

H₂ antagonists: clinical uses

Answer 12

• GERD
  
  • PPIs preferred in severe erosive esophagitis
• Peptic Ulcer Disease
  
  • used at bedtime for noctural acid secretion
• Stress-related gastritis

Question 13

PPIs: Side effects/drug interactions

Answer 13

• mild SE (headache, ab pain, naseau)
  
  • chronic use ==>
    
    • hypergastrinemia
    • rebound gastric acidity after discontinuation
• drug-drug interactions
  
  • CYP450 metabolism ==>
  • omeprazole ==> inhibits conversion of clopidogrel (antiplatet agent) to active form

Question 14

H₂ antagonists: Side effects/drug interactions

Answer 14

• Side effects
  
  • rare and mild (dizzy, diarhea/constipation, HA)
  • some rare CNS/endocrine effects
• drug-drug interactions
  
  • Cimetidine inhibits cytochrome P450 oxidative metabolism ==>
  • increase the effects or toxicity of number of drugs (theophylline, warfarin, phenytoin, carbamazepine, ketoconazole, itraconazole, benzodiazepines).
• All antisecretory agents can decrease ketoconazole absorption by causing an increase in gastric pH.

Question 15

Sucralfate [Carafate]: MOA

Answer 15

• = sulfated disaccharide aluminum salt
• MOA: binds to necrotic ulcer tissue form protective barrier
• used infrequently or an adjunct therapy

Question 16

Misoprostol (Cytotec): MOA

Answer 16

• Prostaglandin (PGE₁) analog
• MOA:
  
  • PGs ==> inhibition of cAMP formation @ parietal cells ==> decreased H⁺ secretion
  • AND stimulate HCO₃^- & mucous formation

Question 17

Misoprostol (Cytotec): Clinical Use

Answer 17

• major indication = NSAID-induced GI ulceration
• rarely used b/c 4x/day dosing + adverse effects

Question 18

Antacids: MOA, pharmacokinetics

Answer 18

• MOA:
  
  • rapidly raise pH of stomach ==> 4-5
• Pharmacokinetics
  
  • nonabsorbable
  • long-acting
• Dosing
  
  • usually titrated to symptom relief
  • ~1-3 hours after meals (food ==> increased duration)

Question 19

Antacids: primary neutralizing ingredients

Answer 19

• calcium
• aluminum
• magnesium
• sodium bicarbonate

Question 20

Calcium (Tums): general characteristics

Answer 20

• MOA: rapid, prolonged neutralization of acid
• Safe, generally non-systemic, not recommended for chronic use
• SE:
  
  • Constipation
  • hypercalcemia / renal calculi (w/chronic use)
  • rebound secretion due to Ca++ effect on gastrin release

Question 21

Aluminum: general characteristics

Answer 21

• MOA:
  
  • antacid
  • binds phosphate in gut
• Widely used
• SE
  
  • constipation
  • Chronic intake ==> CNS toxicity (encephalopathy)

Question 22

Magnesium (Milk of Magnesia): general characteristics

Answer 22

• MOA: antacid
• Use: often combined w/Al or Ca antacids to counteract constipation
• SE
  
  • osmotic diarrhea
  • Avoid use if renal disease present

Question 23

Sodium bicarbonate (baking soda): general characteristics

Answer 23

• MOA: antacid
  
  • Potent and effective
  • evolution of CO2
• SE
  
  • Contraindicated for prolonged therapy due to systemic effects: Na+ overload and alkalosis
• Avoid if: Pregnant, CHF, hypertension, edema, renal failure (i.e., conditions exacerbated by fluid retention)

Question 24

Prokinetic agents: Clinical Use

Answer 24

• empiric and symptoms-based treatment for various disorders of bowel motility [achalasia of esophagus, gastroparesis]
• symptom relief of esophagitis associated with gastroesophageal reflux disease (GERD).

Question 25

Prokinetic agents: examples

Answer 25

• Metoclopramide (Reglan)
• Tegaserod (Zelnorm)
• Cisapride (Propulsid)

Question 26

Metoclopramide: MOA & SE

Answer 26

• MOA: antagonist (-) at presynaptic dopamine (DA) receptors (D2) that inhibit the release of acetycholine
• SE:
  
  • somnolence
  • dystonic reactions
  • tardive dyskinesia

Question 27

Tegaserod (zelnorm) & Cisapride: MOA & SE

Answer 27

• MOA: agonists at postsynaptic 5HT4 receptors to directly increase ACh release
  
  • Stimulates motility and increases transit in esophagus, stomach, small intestine and ascending colon
  • Reduces bloating associated with irritable bowel syndrome
• SE
  
  • Some severe SEs (e.g. MIs, CVAs & arrhythmias) ==> severely restricted use
  • back on market for IBS

Question 28

Erythromycin: MOA

Answer 28

• promotility agent
• MOA: (+) is an agonist at excitatory (+) at neural and smooth muscle motilin receptors

Question 29

Therapeutic targets of anti-emetic agents

Answer 29

• vomiting center/solitary tract nucleus
• afferent inputs to vomiting center:
  
  • chemoreceptor trigger zone/area postrema
    
    • dopamine, 5-HT3, muscarinic, and mu opioid receptors
  • vestibular apparatus
    
    • muscarinic and H₁ receptors
  • vagal/eneteric afferents
    
    • 5-HT₃
  • higher CNS centers

Question 30

Ondansetron [Zofran]: MOA, efficacy, SE

Answer 30

• MOA: Block of serotonin (5-HT3) receptors at chemoreceptor trigger zone (CTZ in CNS), solitary tract nucleus, and on visceral afferents (GI tract
• Clinical use:
  
  • vomiting assoc. w/cytotoxic drugs
  • N/V assoc. w/opioid use
• SE:
  
  • HA, constipation, drowsy
  • QT prolongation

Question 31

Dopamine Receptor Antagonists: : MOA, use, SE

Answer 31

• MOA: Blockade of dopamine receptors in CTZ
• Clinical use:
  
  • prochlorperazine ==> motion sickness
  • metoclipramide ==> N/V w/chemo
• Side effects:
  
  • extrapyramidal symptoms (movement disorders)
  • restlessness, fatigue, drowsiness
  • diarrhea

Question 32

Dopamine Receptor Antagonists: examples

Answer 32

• Metoclopramide [Reglan]
• Phenothiazines:
  
  • Prochlorperazine [Compazine]

Question 33

Metoclopramide [Reglan]: drug category/MOA

Answer 33

• anti-emetic
• MOA: block D receptors @ CTZ

Question 34

Prochlorperazine: drug category/MOA

Answer 34

• anti-emetic
• MOA: block D receptors @ CTZ

Question 35

Antihistamines: MOA, clinical use, examples

Answer 35

• examples: meclizine [Bonine}, diphenhydramine [Dramamine]
• First generation agents with good CNS penetration and additional muscarinic receptor blocking actions
• Primary use for motion sickness and postoperative emesis

Question 36

Anticholinergics: MOA, clinical use, examples

Answer 36

• example: scopolamine [Transderm = transdermal patch]
• Primary use is prevention and treatment of motion sickness; some efficacy in post-operative nausea and vomiting
• Most commonly administered transdermally with duration of action of 72 hours