Acid Blockers & H. Pylori Tx

Question 1

Acid Secretion

Physiology

Answer 1

• Parietal cells ⇒ H⁺ into lumen via H⁺/K⁺ ATPase
  
  • ⊕ by gastrin, ACh, histamine
• Dietary peptides:
  
  • ⊕ Antral G-cells ⇒ gastrin → blood → fundus
    
    • Gastrin ⇒ ⊕ Enterochromaffin (ECL) cells ⇒ histamine
  • ⊕ Parietal cells ⇒ H⁺
• ACh from PNS
  
  • ⊕ ECL cells ⇒ histamine
  • ⊕ Parietal cells ⇒ H⁺
  • ⊕ Antral G-cells ⇒ gastrin
  • ⊗ Antral D-cells ⇒ somatostatin
    
    • Normally acts to ⊗ gastrin release from G-cells

Question 2

Acid Secretion

Modulation

Answer 2

• Luminal H⁺ ⇒ ⊕ antral D-cells ⇒ somatostatin ⇒ ⊗ gastrin secretion from G-cells
• Proteins and fats ⇒ ⊕ duodenal L-cells ⇒ CCK ⇒ ⊕ antral D-cells → secrete somatostatin

Question 3

Histamine H2 Receptor Antagonists

Drugs, MOA, Pharmacokinetics

Answer 3

Cimetidine, Famotidine, Ranitidine

• Mechanism of Action:
  
  • Competitive inhibitor @ H2 receptors on parietal cells
  • ↓ Pepsin release
• Pharmacokinetics:
  
  • T_½ 2-3 hrs but duration of action is much longer
  • Administered 1-2x/day
  • ⊗ meal-stimulated & basal secretion
  • Esp. effective vs nocturnal secretion (dependent on histamine)

Question 4

Histamine H2 Receptor Antagonists

Indications

Answer 4

• Gastroesophageal reflux disease (GERD)
• Laryngopharyngeal reflux (LPR)
• Peptic ulcer disease
  
  • 1-2x/day for 6-8 wks, usu. @ night on empty stomach to suppress nocturnal secretion
  • Tx for H. pylori to prevent relapse after stopping mono tx
• Dyspepsia
  
  • Given 30 mins before a meal
• Stress-related gastritis
  
  • Occurs in critically ill pts d/t impaired mucosal defenses caused by poor perfusion
• Not as effective for erosive esophagitis (PPI preferred)

Question 5

Stress-related Ulcers

Risk Factors

Answer 5

• Mechanical ventilation
• Coagulopathy
• TBI
• Major burn
• ICU pts w/:
  
  • Multiple traumas
  • Sepsis
  • Acute renal failure

Question 6

Histamine H2 Receptor Antagonists

Adverse Effects & Interactions

Answer 6

Cimetidine has unique AE & interactions:

• Anti-androgenic effects
  
  • ♀ ⇒ galactorrhea, amenorrhea
  • ♂ ⇒ gynecomastia
• Potent ⊗ of several cyp450 isozymes ⇒ numerous drug interactions

Question 7

Proton Pump Inhibitors

Drugs, MOA, Pharmacokinetics

Answer 7

• Lansoprazole, Omeprazole, Esomeprazole
• Acid-labile prodrugs ⇒ given as enteric coated tablets
• Uncharged form → parietal cell cytoplasm → acidic canaliculus → active sulfenamide form
• Forms covalent disulfide link w/ luminal cysteinyl in proton pump of parietal cell
  
  • Rxn depends on conformational ∆ of active H⁺/K⁺-ATPase pump
• Food ⇒ ⊕ proton pumps ⇒ PPIs should be taken 30-60 min prior to meals
• Irreversible inhibition ⇒ H⁺ secretion inhibited for an extended time past T_½
  
  • PPI’s suppress H⁺ secretion better and for a longer time than H2 blockers

Question 8

PPIs

Indications

Answer 8

• Peptic ulcer disease
  
  • Slightly more effective than H2 blockers
  • Many pts will relapse if not tx for H. pylori
• NSAID-associated ulcers
• Gastroesophageal reflux disease (GERD)
• Laryngopharyngeal reflux (LPR)
• Zollinger-Ellison syndrome 2/2 gastrin-secreting tumors
• Stress-related gastritis
  
  • Occurs in critically ill pts d/t impaired mucosal defenses 2/2 poor perfusion
  • Immediate release omeprazole maybe preferred in pts w/ NG tube, but otherwise H2 antagonists are preferred
  • Most pts take PO but IV admin allows ↑ [drug] to enter parietal cell w/o degradation
    
    • Used in pts unable to take PO meds that require profound acid suppression

Question 9

Immediate-Release

Omeprazole

Answer 9

• Contains sodium bicarb ⇒ protects uncoated drug from degradation by gastric acid
• Accelerated anti-secretory action may be d/t activation of proton pumps by rapid neutralization of intragastric H⁺ by sodium bicarb

Question 10

PPIs

Adverse Effects

Answer 10

• Generally well-tolerated
• Lack of acidic environment in stomach ⇒ poor absorption of some nutrients
  
  • Ex. calcium ⇒ some ↑ in hip fractures reported
• ↑ Clostridium difficile
• Possible link w/ PNA
• Long-term use ⇒ fundic gland polyposis of stomach
• CKD

Question 11

Rebound Acid Secretion

Answer 11

Seen when stopping after long term use of PPIs

↓ Gastric H⁺ ⇒ disinhibition of G cells ⇒ ↑ gastrin ⇒ bound acid secretion

Question 12

PPIs

Drug Interactions

Answer 12

• Extensively metabolized by the cytochrome p450 system (cyp2C19; cyp3A4)
  
  • 2C19 polymorphism ⇒ slower clearance
• Standards doses of the PPI’s take differences into account, so most pts achieve a therapeutic effect
• Omeprazole may inhibit metabolism of warfarin, diazepam, phenytoin, and carbamazepine
• Clopidrogel prodrug needs cyp450 activation to active form
  
  • Competition ⇒ ↓ efficacy & ↑ risk of MI

Question 13

Gastric Antacids

Answer 13

Aluminum and magnesium hydroxides, calcium carbonate, sodium bicarbonate

• MOA: Neutralizes acid
• Indications:
  
  • Acid indigestion
  • PUD (hard to dose properly)
  • Calcium carbonate also used as a calcium supplement
    
    • Calcium citrate absorbed better in pts on PPI’s
• Adverse Effects:
  
  • Aluminum ⇒ constipation and magnesium ⇒ diarrhea, usually administered together (Maalox, Mylanta)
  • Calcium carbonate and sodium bicarbonate ⇒ transient metabolic alkalosis
    
    • CO₂ liberated can cause flatulence

Question 14

Maalox

Answer 14

• Aluminum hydroxide + Magnesium hydroxide
• Contains Simethicone
  
  • Anti-foaming agent ⇒ ↓ surface tension of gas bubbles ⇒ combines into larger bubbles that pass more easily ⇒ ↑ rate of exit

Question 15

Rolaids

Answer 15

Calcium-carbonate antacid

Also used as a calcium supplementa

Question 16

Alka-Seltzer

Answer 16

Citric acid + sodium bicarbonate antacid

• Compounds react → CO₂ ⇒ flatulence
• Enough sodium bicarb ingested for H⁺ neutralization

Question 17

Sucralfate

Answer 17

Sulfated polysaccharide

Mucosal protective agents

• MOA:
  
  • Adheres to ulcer craters and epithelial cells
  • ⊗ Pepsin-catalyzed hydrolysis of mucosal proteins
  • ↑ Prostaglandin synthesis
    
    • Prostaglandins ⇒ ↓ H⁺ and ↑ mucus production
  • Actions form a protective barrier that allows the ulcer to heal
• Can be used for PUD
  
  • Less effective than H2 blockers and PPI’s
  • Incompatible w/ H2 blockers and PPI’s ⇒ requires acidic environement for activation
• Can ⊗ absorption of other drugs such as digoxin

Question 18

Bismuth Subsalicylate

Answer 18

Mucosal protective agent

• Bismuth effects:
  
  • Anti-secretory ⇒ ⊕ absorption of fluids and electrolytes across intestinal wall
  • Anti-inflammatory ⇒ hydrolyzed to salicylic acid ⇒ ⊗ prostaglandin synthesis (responsible for inflammation and hypermotility)
  • Antimicrobial ⇒ binds toxins secreted by E. coli, other bactericidal properties
  • Relieves nausea and abdominal cramps
• Pepto-Bismol
  
  • Contains clay ⇒ ? benefits in diarrhea
• Kaopectate
  
  • Contains bismuth @ higher concentrations
• Adverse effects:
  
  • Dark stools and black staining of the tongue
    
    • Drug + bacterial sulfides in the GI tract → bismuth sulfide (cause)
  • Contains salicylate ⇒ same warnings as ASA for children & pts allergic to ASA

Question 19

Helicobacter pylori

Overview

Answer 19

• Gram ⊖ helical shaped rod
• Enters GI tract via oral route
• Attaches to adhesion molecules on surface of gastric epithelial cells
• Able to exist in an acidic environment d/t urease production
  
  • Protects bacteria by: Urea → ammonia ⇒ buffers H⁺ → ammonium hydroxide
• Urease, ammonia & factors produced by H. pylori ⇒ damages epithelial lining
• ↑ acid secretion via two mechanisms:
  
  • Urease ⇒ ↑ pH ⇒ ⊕ G-cells to release gastrin
    
    • ↑ Gastrin ⇒ proliferation of parietal cells & ↑ acid secretion
  • Inflammation damages D-cells ⇒ ↓ somatostatin (normally ⊗ gastrin secretion from G-cells)

Question 20

H. pylori

Treatment

Answer 20

H. pylori associated ulcers

• Usually tx w/ combo of PPI + 2 Abx
  
  • Recommended therapy changes often d/t resistance
  • PPI ⇒ ↑ pH ⇒ ↓ MIC for abx
• One typical therapeutic protocol:
  Sequential therapy (for total of 10 days)
  
  • Days 1-5
    
    • PPI ⇒ healing dose BID
    • Amoxicillin 1 g BID
  • Days 6-10
    
    • PPI ⇒ healing dose BID
    • Clarithromycin 500 mg BID
    • Metronidazole 500 mg BID

Question 21

Metronidazole

Answer 21

• Spectrum:
  
  • Anaerobic bacteria
  • Protozoa
  • C. diff
• ⊗ Warfarin metabolism
• Metallic taste
• Class B for pregnancy
• Tinidazole has more mild AEs but class C for pregnancy