What are the mechanism of action, dosing, indications, side effects, and monitoring requirements for Potassium Competitive Acid Blockers (P-CABs), such as vonoprazan (vonoprazan), in the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease?

Potassium-Competitive Acid Blockers (P-CABs): Mechanism, Dosing, Indications, Side Effects, and Monitoring

Potassium-competitive acid blockers (P-CABs) represent a superior alternative to proton pump inhibitors (PPIs) for acid-related disorders, offering more rapid, potent, and sustained acid suppression with fewer limitations than traditional PPIs. 1

Mechanism of Action

P-CABs work through a fundamentally different mechanism than PPIs:

• Binding mechanism: P-CABs bind ionically (reversibly) to the gastric H+/K+-ATPase enzyme, blocking potassium access to the binding site of the proton pump 1
• Unlike PPIs, which:
  • Require conversion from prodrug form in acidic environment
  • Bind covalently (irreversibly) to active pumps
  • Need to be taken 30-60 minutes before meals 1

P-CABs offer several pharmacological advantages:

• Acid-stable compounds (no enteric coating needed)
• Not prodrugs - no conversion required for activation
• Rapid onset of action (2-3 hours) 2
• Longer half-life (6-9 hours vs 1-2 hours for PPIs) 1
• Meal-independent administration (can be taken any time) 1
• Less affected by CYP2C19 polymorphisms that impact PPI metabolism 1
• Maximal acid suppression achieved in 1 day (vs 3-5 days for PPIs) 1

Available P-CABs

Currently available P-CABs include:

• Vonoprazan (FDA approved in US)
• Tegoprazan (available in Latin America)
• Revaprazan, fexuprazan, linaprazan, zastaprazan, and keverprazan (available in various markets) 1, 3

Dosing

For vonoprazan (the most studied P-CAB):

• Erosive esophagitis healing: 20 mg once daily 1, 2
• Maintenance of healed erosive esophagitis: 10 mg once daily 2
• Non-erosive GERD: 10 mg once daily 2
• H. pylori eradication: Part of combination therapy 1, 2

Dosage adjustments:

• Severe renal impairment (eGFR <30 mL/min): Dose reduction recommended for erosive esophagitis; not recommended for H. pylori treatment 2
• Moderate to severe hepatic impairment (Child-Pugh B/C): Dose reduction recommended for erosive esophagitis; not recommended for H. pylori treatment 2

Clinical Indications

P-CABs are indicated for:

1. Erosive esophagitis (EE):

   • Particularly effective for severe grades (LA-C/D) 1, 4
   • Superior healing rates compared to PPIs 1

2. PPI-resistant GERD:

   • High efficacy in healing PPI-resistant EE (91.7% at 4 weeks) 5
   • Good maintenance rates (93.8% at 48 weeks) 5

3. H. pylori eradication:

   • Part of combination therapy 1, 3
   • More effective than PPIs in eradication regimens 3

4. Potential uses (pending more data):

   • On-demand therapy for heartburn 1, 4
   • Barrett's esophagus management 6
   • Peptic ulcer disease 1

Side Effects

P-CABs are generally well-tolerated with safety profiles comparable to PPIs in short-term studies 1:

• Common side effects: Similar to PPIs (headaches, diarrhea, constipation, nausea) 7
• Hypergastrinemia: More pronounced than with PPIs 1, 8
  • Serum gastrin levels increase and remain elevated during treatment
  • Return to normal within 4 weeks after discontinuation 2
• Potential concerns (similar to PPIs):
  • Clostridioides difficile infection (comparable risk to PPIs) 1
  • Possible increased risk of gastric cancer (hazard ratio <2, similar to PPIs) 1
  • Enterochromaffin-like cell hyperplasia (infrequent) 1
  • Increased CgA levels that may cause false positive results in neuroendocrine tumor testing 2

Monitoring

When using P-CABs, clinicians should:

1. Before initiation:

   • Assess renal and hepatic function to determine appropriate dosing 2
   • Consider testing for H. pylori in patients with peptic ulcer disease 7

2. During treatment:

   • Monitor for symptom improvement
   • Be aware of potential drug interactions (though fewer than with PPIs) 1
   • Consider that elevated gastrin levels are expected 2

3. Long-term use:

   • Regular reassessment of ongoing indications 7
   • Consider potential for false positive neuroendocrine tumor tests due to elevated CgA levels 2

Clinical Pearls and Pitfalls

• P-CABs should be used in patients with severe erosive esophagitis (LA-C/D) who fail PPI therapy 1
• P-CABs may not be necessary as first-line therapy for milder forms of GERD (LA-A/B) 1
• Avoid inappropriate long-term use without periodic reassessment 7
• Be aware that P-CABs cause more pronounced hypergastrinemia than PPIs 1, 8
• Consider P-CABs for patients with nighttime acid breakthrough on PPIs due to better control of nighttime acid secretion 6

P-CABs represent a significant advancement in acid suppression therapy, particularly for patients with severe or PPI-resistant acid-related disorders.