Gastroenterology · Medicine Class

Proton Pump Inhibitors (PPIs)

Irreversible inhibition of H+/K+ ATPase (the proton pump)

Mechanism of Action

PPIs are prodrugs that require acid-catalyzed activation to sulfenamide form in the canaliculi of gastric parietal cells. The activated medicine irreversibly binds and inhibits H+/K+ ATPase — the final step in gastric acid secretion. Because they irreversibly bind the pump, acid suppression persists until new pumps are synthesized (24-48 hours). This explains why morning (pre-breakfast) dosing is optimal — it catches the most newly synthesized pumps at peak activation.

Therapeutic Indications

Gastroesophageal reflux disease (GERD)
Peptic ulcer disease (gastric and duodenal ulcers)
H. pylori eradication (component of triple/quadruple therapy)
NSAID-associated ulcer prevention (high-risk patients)
Zollinger-Ellison syndrome
Barrett's esophagus
GI bleeding prophylaxis in ICU (stress ulcer prophylaxis)
Eosinophilic esophagitis

Medicines in This Class

Omeprazole (Prilosec)

Original PPI; generic available; OTC 20mg. Most CYP2C19 interactions. Racemic mixture.

Esomeprazole (Nexium)

S-isomer of omeprazole; modest efficacy advantage claimed. OTC 20mg available.

Pantoprazole (Protonix)

Fewest CYP interactions — preferred with clopidogrel. IV formulation available. Widely used in hospitals.

Lansoprazole (Prevacid)

OTC available; disintegrating tablet form. Orally disintegrating tablet useful for NG tube.

Dexlansoprazole (Dexilant)

Dual delayed-release; can be taken without regard to meals. Higher cost.

Rabeprazole (Aciphex)

Less CYP2C19 metabolism; more consistent effect in poor metabolizers.

Class-Wide Side Effects

Common Side Effects

Headache (most common)
Diarrhea, nausea, abdominal pain
Flatulence

Serious Side Effects

Clostridium difficile infection — acid suppression alters gut microbiome; 65% increased risk
Hypomagnesemia — symptomatic with >1 year use; can cause tetany, arrhythmias
Vitamin B12 deficiency — impaired acid-dependent absorption
Bone fractures — modest increased risk with high-dose, long-term use
Acute interstitial nephritis — rare but recognized association
Potential CKD risk — observational data; causation uncertain

Class Medicine Interactions

Clopidogrel (Plavix) — omeprazole/esomeprazole inhibit CYP2C19 activation; pantoprazole preferred

Methotrexate — PPIs reduce renal elimination → methotrexate toxicity (especially high-dose MTX)

Atazanavir — requires acid for absorption; PPIs reduce atazanavir levels significantly

Rilpivirine — same issue as atazanavir; PPIs contraindicated

Iron, ketoconazole, itraconazole — reduced absorption with acid suppression

Contraindications

!Concurrent atazanavir or rilpivirine use
!Known hypersensitivity to PPIs
!Long-term use without ongoing indication

Monitoring Parameters

Reassess indication periodically (PPIs are often continued indefinitely without ongoing need)
Serum magnesium: baseline and periodically with long-term use
Vitamin B12: consider in patients on PPIs >2 years
Renal function: especially in patients with risk factors

Frequently Asked Questions

Do PPIs cause cancer?

Observational studies have raised concerns about gastric cancer with long-term PPI use, particularly in H. pylori-infected patients. Eradicating H. pylori before or during PPI therapy is important. The absolute risk increase is small for most patients. Randomized trial data do not show a causal cancer signal for standard-indication, appropriate-duration PPI use.

Can I take PPIs while pregnant?

Omeprazole and esomeprazole are FDA Category C (insufficient human data; animal toxicity at high doses). Pantoprazole, lansoprazole, and rabeprazole are also Category B/C. If GERD treatment is needed in pregnancy and H2 blockers fail, PPIs can be used — famotidine (H2 blocker) is generally preferred first. Most professional societies consider PPIs acceptable when clinically indicated.