Mechanism of Action of Famotidine
Famotidine is a competitive inhibitor of histamine-2 (H2) receptors on gastric parietal cells, blocking histamine-mediated stimulation of gastric acid secretion, thereby suppressing both the acid concentration and volume of gastric secretion. 1
Primary Pharmacologic Mechanism
- Famotidine competitively blocks histamine at H2 receptors on parietal cells, preventing histamine from binding and initiating the cascade that leads to gastric acid production 1, 2
- The drug specifically targets the H2 subtype of histamine receptors, which are distinct from H1 receptors involved in allergic responses 2
- Acid suppression occurs for both basal (unstimulated) and stimulated gastric secretion, including secretion triggered by food, pentagastrin, and nocturnal acid production 1, 3
- Pepsin secretion changes are proportional to the reduction in gastric volume output 1
Comparative Potency
- Famotidine is 20-32 times more potent than cimetidine on a weight basis 4, 5, 6
- Famotidine is 7.5-9 times more potent than ranitidine 4, 5, 6
- This higher potency translates to lower required doses and potentially longer duration of action compared to other H2 receptor antagonists 5
Pharmacodynamic Profile
Onset and Duration
- Antisecretory effect begins within 30 minutes to 1 hour after oral administration 7, 1, 3
- Peak effect occurs 1-3 hours (specifically 2.5 hours) after dosing, with maximum plasma concentrations reached at this time 8, 7, 1
- Duration of acid inhibition is 10-12 hours for standard doses (20-40 mg), making twice-daily dosing effective 8, 7, 1
- Famotidine has a 30% longer duration of action compared to cimetidine or ranitidine 5, 6
Degree of Acid Suppression
- Evening doses of 20 mg and 40 mg inhibit nocturnal gastric acid secretion by 86% and 94%, respectively, for at least 10 hours 1
- Morning doses suppress food-stimulated acid secretion by 76% and 84% at 3-5 hours post-administration 1
- Nocturnal intragastric pH is raised to mean values of 5.0 (20 mg dose) and 6.4 (40 mg dose) 1
- In pediatric patients, famotidine at 0.5 mg/kg maintains gastric pH above 5 for 13.5 ± 1.8 hours 1
Clinical Implications of Mechanism
Advantages Over Other H2 Antagonists
- Famotidine does not bind to the cytochrome P-450 system, unlike cimetidine, eliminating drug-drug interactions through hepatic metabolism 8, 9, 3, 6
- No antiandrogenic effects are observed with famotidine, unlike cimetidine which can cause gynecomastia 8, 6
- Famotidine does not interfere with clopidogrel's antiplatelet activity, making it the preferred H2 antagonist for patients on dual antiplatelet therapy 9, 10
Limitations of H2 Receptor Blockade
- Tachyphylaxis develops within 6 weeks of continuous use, limiting long-term effectiveness as tolerance to acid suppression develops 8, 9, 7
- H2 receptor antagonists work best as prophylactic rather than acute treatment, since they cannot block histamine already bound to receptors 8
- H2 antagonists are less effective than proton pump inhibitors for healing erosive esophagitis and providing symptom relief in GERD 8
Specific Clinical Applications
- For patients on dual antiplatelet therapy (aspirin plus clopidogrel), famotidine is recommended over PPIs by the American College of Cardiology due to lack of CYP2C19 interaction 8, 9, 10
- In mast cell activation syndrome, H2 blockers like famotidine prevent histamine-mediated acid secretion from parietal cells and blunt vasoactive effects when combined with H1 antagonists 8
- Famotidine is effective for treating abdominal and vascular symptoms in conditions involving histamine release 8