Mechanism of Rifaximin in Treating Hepatic Encephalopathy
Rifaximin treats hepatic encephalopathy primarily by inhibiting bacterial RNA synthesis in the gut, reducing ammonia-producing bacteria without being systemically absorbed, thereby decreasing ammonia levels that contribute to hepatic encephalopathy. 1
Primary Mechanism of Action
- Rifaximin is a semi-synthetic, non-absorbable antibiotic derived from rifamycin SV that binds to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking transcription and inhibiting bacterial protein synthesis 1
- It maintains high concentrations in the intestine with minimal systemic absorption, allowing it to effectively target gut bacteria without significant systemic side effects 2, 1
- Rifaximin has broad antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative bacteria in the intestinal tract 2
Effects on Gut Microbiota and Ammonia Production
- Rifaximin modulates the gut microbiota without significantly altering overall microbial diversity or composition, which helps maintain gut homeostasis while targeting pathogenic bacteria 3
- It reduces intestinal production and absorption of ammonia by altering gastrointestinal flora that produce ammonia from protein breakdown 4
- Elevated ammonia levels are seen in more than 80% of patients with hepatic encephalopathy, making ammonia reduction a key therapeutic target 4
Metabolic Pathway Alterations
- Rifaximin treatment leads to reduced expression of several metabolic pathways related to hepatic encephalopathy, including: 3
- Aromatic amino acid metabolism
- Tryptophan synthesis
- Urea cycle pathways
- Lipopolysaccharide (LPS) synthesis
Complementary Effects with Lactulose
- When used in combination with lactulose (the first-line treatment), rifaximin provides synergistic effects: 5, 2
- Lactulose reduces intestinal pH through bacterial degradation, converting ammonia to less absorbable ammonium
- Rifaximin directly reduces ammonia-producing bacteria
- Together they more effectively reduce ammonia levels than either agent alone
Clinical Evidence Supporting Mechanism
- Studies show rifaximin improves cognitive function and reduces hyperammonemia in patients with hepatic encephalopathy 3
- Rifaximin maintains remission from hepatic encephalopathy more effectively than placebo over a 6-month period (hazard ratio 0.42; 95% CI, 0.28 to 0.64) 6
- Unlike other antibiotics used for hepatic encephalopathy (neomycin, metronidazole), rifaximin has minimal systemic absorption, reducing risk of ototoxicity, nephrotoxicity, and neurotoxicity with long-term use 5
Resistance Concerns
- Despite being an antibiotic, long-term prophylactic use (12 weeks) did not significantly change the overall resistome or lead to emergence of new antimicrobial resistance genes 3
- Clinical studies have not demonstrated increased risk of Clostridium difficile infection with rifaximin treatment compared to control groups 5
Clinical Application
- Rifaximin is recommended as an effective add-on therapy to lactulose for prevention of overt hepatic encephalopathy recurrence (Grade I, A, 1) 5
- The typical dosage is 550 mg twice daily or 400 mg three times daily 2, 4
- Rifaximin is particularly valuable for patients who have experienced one or more episodes of overt hepatic encephalopathy while on lactulose treatment 5
By targeting gut bacteria and reducing ammonia production through multiple mechanisms, rifaximin effectively treats hepatic encephalopathy while maintaining a favorable safety profile for long-term use.