H2 antagonists

• Definition

• H2 antagonists, also known as histamine H2-receptor antagonists or H2 blockers, are a class of drugs that reduce gastric acid secretion by competitively blocking histamine at the H2 receptors of the parietal cells in the stomach lining

• They are used primarily in the treatment and prevention of acid-related gastrointestinal disorders

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• Mechanism of Action

• In the stomach, histamine binds to H2 receptors on gastric parietal cells, activating adenylate cyclase and increasing intracellular cyclic AMP (cAMP)

• Increased cAMP stimulates the proton pump (H⁺/K⁺-ATPase) to secrete hydrogen ions (acid) into the gastric lumen

• H2 antagonists compete with histamine for binding at the H2 receptors, blocking histamine-mediated stimulation of acid secretion

• This results in reduced basal, nocturnal, and meal-stimulated gastric acid output

• They do not significantly affect H1 or H3 histamine receptors

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• Common Agents

• Ranitidine (formerly widely used; withdrawn in many markets due to NDMA contamination concerns)

• Famotidine – potent and well tolerated; preferred in many guidelines

• Nizatidine – similar efficacy; less frequently used

• Cimetidine – oldest in class; effective but associated with more drug interactions and hormonal side effects

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• Therapeutic Uses

• Treatment and maintenance therapy of peptic ulcer disease (gastric and duodenal ulcers)

• Management of gastroesophageal reflux disease (GERD)

• Relief of heartburn, acid indigestion, and sour stomach (OTC formulations)

• Prevention of stress-related mucosal damage in critically ill patients (stress ulcer prophylaxis)

• Treatment of Zollinger–Ellison syndrome (less preferred than proton pump inhibitors)

• Part of combination regimens for H. pylori eradication (less common today)

• Preoperative prophylaxis to reduce gastric acidity and volume before anesthesia in high-risk patients

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• Dosage Examples

• Famotidine:

  • GERD: 20 mg orally twice daily or 40 mg once daily

  • OTC heartburn: 10–20 mg as needed before or after meals

• Nizatidine: 150 mg orally twice daily or 300 mg once daily at bedtime

• Cimetidine: 400 mg twice daily or 800 mg at bedtime (higher doses for Zollinger–Ellison syndrome)

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• Contraindications

• Known hypersensitivity to H2 antagonists

• Caution in patients with a history of acute porphyria (rare reports with cimetidine)

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• Adverse Effects

1. Common (generally mild and infrequent)

   • Headache

   • Dizziness

   • Diarrhea or constipation

   • Fatigue

2. Less common but notable

   • Mental status changes (confusion, hallucinations) in elderly or critically ill patients, especially with IV cimetidine or renal impairment

   • Gynecomastia and impotence with high-dose or long-term cimetidine (due to antiandrogenic effects)

   • Vitamin B12 deficiency with prolonged use (rare)

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• Precautions

• Dose adjustment required in moderate to severe renal impairment (creatinine clearance <50 mL/min)

• Cimetidine should be avoided or used with caution in patients taking drugs metabolized by CYP450 enzymes

• Prolonged use may mask symptoms of gastric malignancy; evaluate unexplained dyspepsia before initiating long-term therapy

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• Drug Interactions

• Cimetidine: Potent inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, increasing plasma concentrations of drugs such as warfarin, theophylline, phenytoin, lidocaine, and tricyclic antidepressants

• Famotidine and nizatidine have minimal CYP450 interactions and are preferred in patients on multiple medications

• May affect absorption of drugs where gastric pH is important (e.g., ketoconazole, atazanavir)

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• Clinical Considerations

• Onset of action: ~1 hour; duration of effect: 6–12 hours (longer with famotidine)

• For rapid relief, may be taken before anticipated acid exposure (e.g., before meals)

• Proton pump inhibitors are generally more effective for severe acid suppression, but H2 antagonists remain useful for mild-to-moderate symptoms and for nocturnal acid control

• Tolerance (tachyphylaxis) may develop with continuous use beyond a few weeks, especially for nighttime acid suppression

• Famotidine is often used in dual therapy with PPIs for refractory GERD to control nocturnal acid breakthrough