Medications Harming Your Digestive Health – Voquezna (Vonoprazan, P-CABs)

Many people worldwide are still suffering from reflux disorders. A new class of acid-reducing medications, Potassium-competitive acid blockers (P-CABs), has been approved by the United States Food and Drug Administration for heartburn relief. Previous acid-reducing medications, including Proton Pump Inhibitors (PPIs), are known to have numerous side effects. Is the P-CAB Voquezna (vonoprazan) any safer than Prilosec or Nexium?

Proton Pump Inhibitors (PPIs)

Proton pump inhibitors (PPIs) irreversibly drastically limit acid production for days within our stomach. PPIs work by irreversibly binding to and blocking the hydrogen/potassium adenosine triphosphatase (H⁺/K⁺‑ATPase) enzyme system located on the secretory surface of gastric parietal cells. By shutting down this “proton pump,” which is the final step in the pathway of gastric acid secretion, PPIs drastically reduce the amount of hydrochloric acid released into the stomach lumen, leading to a sustained and significant decrease in gastric acidity. This enzymatic system, or proton pump, is directly responsible for secreting hydrogen ions into our gastric lumen, producing stomach acid. PPIs require a low pH to be converted to their active sulfenamide form within our gastric parietal cells, which is why they should be taken right before eating breakfast, since eating stimulates stomach acid production. PPIs take two to three days to inactivate enough proton pumps within our stomach to reduce stomach acid production significantly. This mechanism is reversed two to three days after the medication is stopped. Proton pump inhibitors are more potent and longer-acting than H2 antagonists like Pepcid.^{1 2}

Potassium-Competitive Acid Blocker (P-CAB) Mechanism of Action

Potassium-competitive acid blockers (P-CABs), like Voquezna (vonoprazan), unlike PPIs, reversibly and dramatically limit acid production within our stomach for days. P-CABs reduce stomach acid by reversibly inhibiting the gastric proton pump (H⁺/K⁺‑ATPase) within our stomach’s parietal cells. P-CABs work by competing with potassium ions for binding sites on the pump, thereby blocking the exchange of hydrogen and potassium ions that typically drives acid secretion. P-CABs directly and reversibly block the potassium-binding site of the proton pump, allowing them to inhibit both active and resting proton pumps without stomach acid activation. Because P-CABs bypass the slow, pH-dependent activation step required by PPIs, P-CABs achieve rapid and consistent acid suppression within hours rather than days.³

The liver enzyme CYP2C19 mainly metabolizes PPIs, and genetic polymorphisms in this gene strongly influence their effectiveness. For example, individuals with CYP2C19 poor metabolizer alleles have higher drug levels and stronger acid suppression, while ultra-rapid metabolizers clear PPIs too quickly, leading to reduced efficacy. In contrast, P-CABs are not metabolized by CYP2C19, so CYP2C19 does not affect their acid-suppressing effect polymorphisms. PPIs exhibit greater pharmacodynamic effects during the daytime because they require a low stomach pH and active proton pumps for activation, which usually occur during and after meals. In contrast, P-CABs act directly on the pump and therefore maintain potent acid suppression consistently throughout both day and night. P-CABs are more efficient in reducing acid within our stomach, but how does their side effect profile compare to PPIs?⁴

Potassium-Competitive Acid Blocker (P-CAB) Side Effects

Since potassium-competitive acid blockers (P-CABs), like Voquezna (vonoprazan), and PPIs both inhibit the gastric proton pump and drastically reduce stomach acid production, they both have roughly the same frequency and severity of side effects. “In terms of safety, there was no significant difference in adverse events between PCABs and PPIs (OR: 0.91, 95% CI: 0.79-1.04, p=0.18), including serious adverse events.” Because PCABs are more potent and fast-acting in reducing stomach acid, their side effects might be more frequent and more significant, in my opinion.

Short-term (less than two weeks) usage of PPIs and PCABs is tolerated, and side effects include headache, gastritis, nausea, vomiting, flatulence, burping, bloating, diarrhea, constipation, abdominal pain, worsening reflux, fatigue, hypertension, urinary tract infection, vaginal yeast infection, brain fog, and dizziness. Rarely, allergic reactions, including rashes and anaphylaxis, may occur.⁵

On the other hand, long-term usage of PPIs and PCABs has an increased risk of side effects, some severe, and they should only be used when all other options have been exhausted. After long-term use, potassium-competitive acid blockers may cause calcium deficiency, magnesium deficiency (especially if you are taking the medication digoxin),⁶ iron deficiency (leading to anemia), zinc deficiency (leading to low levels of testosterone in men),⁷ B12 deficiency (from PCABs hindering production of your stomach’s intrinsic factor),⁸ vitamin C deficiency, Small Intestinal Bacterial Overgrowth (SIBO),⁹ increased risk of developing C. diff dysbiosis,¹⁰ accelerated skin aging,¹¹ Stevens-Johnson or TEN syndrome, bone fractures,¹² increased risk of community-acquired pneumonia,¹³ development of food allergies,¹⁴ acute tubulointerstitial nephritis (leading to acute or chronic kidney failure), gastroparesis, upper gut dysbiosis, hindered mitochondrial health (supplementing with Ubiquinol might help prevent and relieve this side effect), increased risk of gastric cancer, developing or worsening dementia, developing or worsening Alzheimer’s Disease, developing or worsening cardiovascular disease, and even developing or worsening heart arrhythmia.^{15 16}

The risk of SIBO increases when taking PCABs because opportunistic bacteria, which are usually reduced by stomach acid, survive and colonize our small intestine. The survival of excess microorganisms is the reason for the increased risk of community-acquired pneumonia and C. diff in people who take PCABs. Bone fractures and osteoporosis risk increase because the disruption of acid production interferes with bone mineralization. The rise in heart arrhythmias associated with PCAB use is related to decreased magnesium levels within our bodies.

Fix Your Gut Recommendations

PCABs might be more effective in reducing stomach acid than PPIs; however, they have the same, if not worse, side effect frequency and severity. I still do not, however, recommend their use for the average person suffering from heartburn or GERD. If I had to use a PCAB long-term for specific medical reasons (Zollinger-Ellison syndrome for example), I would take a digestive enzyme like Now Pancreatin with every meal. Intuitively, PCABs might also reduce potassium absorption more than PPIs, but time will tell whether that is true.  I would also take an excellent sublingual B12 supplement, take Epsom salt baths frequently, and supplement with magnesium. I would monitor my body’s storage levels of vitamin C, calcium, iron, potassium, and zinc, and supplement when necessary. I would also take certain supplements and make lifestyle changes to stave off osteoporosis, including getting proper sunlight exposure, following the Perfect Health Diet, and supplementing with vitamin K2, boron, calcium, magnesium, and potassium when needed. Finally, if you start to develop H. pylori dysbiosis symptoms, such as increased bloating and belching, I would follow my H. pylori protocol.

When someone attempts to stop long-term PCAB use, rebound reflux occurs, sometimes quite severely. Slowly tapering off PCABs might be necessary to reduce rebound reflux symptoms. Discuss a tapering dosage schedule with your healthcare professional. A basic tapering plan would be taking a PCAB every other day for a few weeks, then every third day for a few weeks, then every fourth day for a few weeks, then every fifth day for a few weeks, and then stop. Taking digestive enzymes like Now Pancreatin with meals may help with the medication tapering period. Making your stomach acidic during meals using betaine HCL also helps improve digestion. Eating smaller meals and consuming less than 10 ounces of water with each meal might help. Most of your water consumption should be in between meals. Do not eat any food three hours before bed when possible. Going on a low-acid diet to prevent further esophageal inflammation can be helpful. Using a supplement like Reflux Raft when rebound reflux is at its worst can also help get relief.

PCABs are quite harmful medications when used long-term, and they are over-prescribed. Unlike Miralax and Reglan, both medicines that should be used sparingly, PCABs are indicated in specific medical circumstances, including severe esophageal/gastric inflammation, esophageal/gastric perforations, esophageal/stomach surgery, or Zollinger-Ellison syndrome. Most doctors prescribe PCABs and PPIs like they are candy if you are suffering from heartburn or GERD. PCABs are just a bandage for your GERD; therefore, they should only be used acutely.

Suppose you are on PCABs or PPIs and address the deficiencies they cause. In that case, I recommend talking to your medical professional about tapering off your PCAB, and/or trying to “fix” your digestive issues. Contact me for coaching if you are suffering from reflux, want to stop taking your PCAB or PPI, or are experiencing rebound reflux after trying to stop your PCAB or PPI.