Proton pump inhibitors – mechanism, SAR, uses MCQs With Answer

Proton pump inhibitors (PPIs) are a vital class of antisecretory drugs that irreversibly inhibit the gastric H+/K+-ATPase in parietal cells, reducing acid secretion. Structurally, PPIs are substituted benzimidazoles linked through a sulfinyl group to a pyridine; key SAR features include pyridine basicity, benzimidazole substitution patterns, and the sulfoxide chiral center that enable acidic activation to a reactive sulfenamide. Clinically used for peptic ulcer disease, GERD, H. pylori eradication adjunct therapy, Zollinger–Ellison syndrome, and stress ulcer prophylaxis, PPIs show CYP-mediated metabolism (notably CYP2C19/CYP3A4) and important adverse effects such as hypomagnesemia and increased C. difficile risk. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. Which functional groups define the core structure of most proton pump inhibitors?

• Substituted benzimidazole linked to a pyridine via a sulfinyl group
• Benzodiazepine ring attached to an imidazole via an ether bond
• Quinolone core with a piperazine side chain
• Sulfonylurea linked to a benzene ring

Correct Answer: Substituted benzimidazole linked to a pyridine via a sulfinyl group

Q2. The pharmacological target of PPIs is:

• H2 histamine receptor on parietal cells
• Gastrin receptor on G cells
• H+/K+-ATPase (proton pump) on parietal cell canaliculi
• M1 muscarinic receptor on chief cells

Correct Answer: H+/K+-ATPase (proton pump) on parietal cell canaliculi

Q3. PPIs are administered as prodrugs because:

• They are unstable in acidic environment and must be converted to active form in parietal cell canaliculi
• They are highly active in plasma and need activation in the liver
• They are only absorbed after enterohepatic recycling
• They require activation by bacterial enzymes in the gut

Correct Answer: They are unstable in acidic environment and must be converted to active form in parietal cell canaliculi

Q4. Activation of PPIs in the acidic canaliculus leads to formation of which reactive intermediate that binds the proton pump?

• Sulfenamide that forms a covalent bond with cysteine residues
• Free radical that alkylates lysine residues
• Carbocation that methylates histidine residues
• Nitrenium ion that binds to serine residues

Correct Answer: Sulfenamide that forms a covalent bond with cysteine residues

Q5. The irreversible nature of PPI inhibition is due to:

• Covalent modification of cysteine residues on the H+/K+-ATPase
• Competitive reversible binding at the active site
• Desensitization of histamine receptors
• Long plasma half-life preventing dissociation

Correct Answer: Covalent modification of cysteine residues on the H+/K+-ATPase

Q6. Which cysteine residue on the H+/K+-ATPase is commonly targeted by activated PPIs?

• Cys813 (numbering may vary by species) near the pump active region
• Cys100 in the ATP-binding site of the pump
• Cys45 in the N-terminal signal peptide
• Cys250 in the luminal glycosylation domain

Correct Answer: Cys813 (numbering may vary by species) near the pump active region

Q7. Which structural feature most influences the pKa and activation site of PPIs?

• Pyridine ring basicity and substituents
• Benzimidazole carbonyl group
• Alkyl chain length on benzimidazole
• Sugar moiety attached to the molecule

Correct Answer: Pyridine ring basicity and substituents

Q8. Which PPI is the S-enantiomer formulated to reduce interindividual variability?

• Esomeprazole
• Omeprazole
• Lansoprazole
• Rabeprazole

Correct Answer: Esomeprazole

Q9. Omeprazole is primarily metabolized by which cytochrome P450 enzyme that causes genetic variability in response?

• CYP2C19
• CYP1A2
• CYP2D6
• CYP2E1

Correct Answer: CYP2C19

Q10. Which PPI is known for having relatively fewer CYP2C19-mediated drug interactions?

• Pantoprazole
• Omeprazole
• Esomeprazole
• Dexlansoprazole

Correct Answer: Pantoprazole

Q11. Clinically, PPIs are first-line therapy for which condition?

• Gastroesophageal reflux disease (GERD)
• Irritable bowel syndrome
• Acute pancreatitis
• Small intestinal bacterial overgrowth

Correct Answer: Gastroesophageal reflux disease (GERD)

Q12. Long-term PPI therapy is associated with which nutritional deficiency risk?

• Vitamin B12 deficiency due to reduced gastric acid
• Vitamin C deficiency due to decreased absorption
• Niacin deficiency due to altered metabolism
• Excess vitamin D absorption

Correct Answer: Vitamin B12 deficiency due to reduced gastric acid

Q13. Which adverse effect has been linked with prolonged high-dose PPI use?

• Hypomagnesemia
• Acute hemolysis
• Hyperkalemia
• Lactic acidosis

Correct Answer: Hypomagnesemia

Q14. For Helicobacter pylori eradication, PPIs are used primarily to:

• Increase gastric pH to enhance antibiotics’ stability and effectiveness
• Directly kill H. pylori through bactericidal action
• Neutralize bile salts that harbor bacteria
• Activate pepsin to digest bacterial cell walls

Correct Answer: Increase gastric pH to enhance antibiotics’ stability and effectiveness

Q15. Which statement about PPI dosing relative to meals is correct?

• PPIs should be taken 30–60 minutes before a meal to maximize pump activation and uptake
• PPIs must be taken immediately after a meal to be effective
• PPIs are ineffective if taken with food
• Timing relative to meals has no impact on PPI efficacy

Correct Answer: PPIs should be taken 30–60 minutes before a meal to maximize pump activation and uptake

Q16. Which PPI undergoes significant non-enzymatic reduction and shows less CYP-mediated variability?

• Rabeprazole
• Esomeprazole
• Omeprazole
• Dexlansoprazole

Correct Answer: Rabeprazole

Q17. Structure–activity relationship: oxidation state of sulfur (sulfoxide vs sulfide) in PPIs is important because:

• Sulfoxide is required for acidic conversion to active sulfenamide
• Sulfide directly inhibits the pump without activation
• Sulfoxide makes the drug water-insoluble and inactive
• Sulfoxide prevents PPI absorption in the intestine

Correct Answer: Sulfoxide is required for acidic conversion to active sulfenamide

Q18. Which clinical syndrome often requires high-dose PPI therapy due to extreme acid hypersecretion?

• Zollinger–Ellison syndrome
• Crohn’s disease
• Achalasia
• Scleroderma

Correct Answer: Zollinger–Ellison syndrome

Q19. Which of the following best describes the duration of acid suppression after a single PPI dose?

• 24–48 hours due to irreversible pump inhibition until new pumps are synthesized
• 2–4 hours similar to H2 blockers
• One week due to tissue accumulation
• Less than one hour owing to rapid clearance

Correct Answer: 24–48 hours due to irreversible pump inhibition until new pumps are synthesized

Q20. Which drug interaction is of concern when PPIs are coadministered with clopidogrel?

• CYP2C19-mediated reduction in clopidogrel activation leading to decreased antiplatelet effect
• PPIs increase clopidogrel bioavailability causing bleeding
• Competition for P-glycoprotein leading to increased clopidogrel excretion
• Activation of clopidogrel by PPIs causing toxic metabolites

Correct Answer: CYP2C19-mediated reduction in clopidogrel activation leading to decreased antiplatelet effect

Q21. Which PPI is commonly available as an enteric-coated delayed-release formulation to prevent gastric degradation?

• Lansoprazole
• Ranitidine
• Cimetidine
• Sucralfate

Correct Answer: Lansoprazole

Q22. Which laboratory monitoring may be indicated for patients on long-term high-dose PPIs?

• Serum magnesium levels
• Complete blood count weekly
• Serum amylase monthly
• Urine protein creatinine ratio

Correct Answer: Serum magnesium levels

Q23. Which PPI is the R-enantiomer of omeprazole marketed separately for modified effect?

• Dexlansoprazole is an R-enantiomer derivative used for dual delayed release
• Esomeprazole is the R-enantiomer of omeprazole
• Pantoprazole is the R-enantiomer of omeprazole
• Rabeprazole is the R-enantiomer of omeprazole

Correct Answer: Dexlansoprazole is an R-enantiomer derivative used for dual delayed release

Q24. Which of the following mechanisms explains increased risk of gastrointestinal infections with PPIs?

• Reduced gastric acidity lowers barrier to pathogens like C. difficile
• PPIs directly suppress immune cell function in the gut
• PPIs increase gastric motility promoting pathogen spread
• PPIs increase bile acid secretion that fosters pathogens

Correct Answer: Reduced gastric acidity lowers barrier to pathogens like C. difficile

Q25. In SAR of PPIs, electron-donating substituents on the benzimidazole ring typically:

• Enhance acid stability and influence activation kinetics
• Prevent prodrug activation in parietal cells
• Convert the drug to an H2 antagonist
• Make the molecule completely hydrophilic

Correct Answer: Enhance acid stability and influence activation kinetics

Q26. Which PPI has a dual delayed-release formulation designed to extend acid suppression?

• Dexlansoprazole
• Omeprazole
• Rabeprazole
• Lansoprazole

Correct Answer: Dexlansoprazole

Q27. Which statement about rebound acid hypersecretion after stopping PPIs is correct?

• Discontinuation can cause temporary rebound acid hypersecretion due to hypergastrinemia
• Stopping PPIs immediately cures GERD without symptoms
• Rebound acidity is permanent and irreversible
• Rebound effect is solely due to bacterial overgrowth

Correct Answer: Discontinuation can cause temporary rebound acid hypersecretion due to hypergastrinemia

Q28. Which clinical use is NOT an approved indication for PPIs?

• Routine treatment of acute uncomplicated diarrhea
• Treatment of erosive esophagitis
• Prevention of NSAID-associated gastric ulcers
• Adjunct in H. pylori eradication therapy

Correct Answer: Routine treatment of acute uncomplicated diarrhea

Q29. What is a key difference in metabolic pathway between omeprazole and pantoprazole relevant to drug interactions?

• Pantoprazole is less dependent on CYP2C19 metabolism, reducing drug–drug interactions
• Omeprazole is exclusively excreted unchanged in urine
• Pantoprazole requires activation by gut bacteria
• Omeprazole is metabolized only by CYP3A4

Correct Answer: Pantoprazole is less dependent on CYP2C19 metabolism, reducing drug–drug interactions

Q30. Which laboratory finding might suggest chronic PPI-related malabsorption complication?

• Low serum vitamin B12 levels
• Elevated serum calcium levels
• High serum magnesium levels
• Increased hemoglobin A1c

Correct Answer: Low serum vitamin B12 levels

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