Ursodeoxycholic Acid (UDCA), Pancreatin and Rifaximin

Mechanism

Mechanism of action

Ursodeoxycholic acid (UDCA): It is a hydrophilic tertiary bile acid that is found naturally in minimal proportions (< 5%) in the bile acid pool of human bile. Its chronic exogenous administration competitively displaces highly toxic hydrophobic and lipophilic primary and secondary bile acids (such as deoxycholic acid and lithocholic acid) from the pool.

Additionally, UDCA stimulates the secretion of bicarbonate and chloride into the lumen of the bile duct, protects cholangiocytes and hepatocytes from apoptosis induced by toxic salts and exerts local immunomodulatory effects.

Pancreatin (Pancreatic Enzymes - Lipase, Amylase, Protease): It is obtained from pancreatic tissue of porcine origin. It contains natural digestive enzymes that hydrolyze fats to fatty acids and glycerol (lipase), starch to dextrins and maltose (amylase), and proteins to active peptides and free amino acids (protease), restoring normal digestion of nutrients in the lumen of the duodenum.

Rifaximin: It is a semi-synthetic antibiotic derived from rifamycin. It irreversibly binds to the beta subunit of the bacterial DNA-dependent RNA polymerase enzyme, inhibiting nucleotide transcription and bacterial protein synthesis.

Pharmacokinetics

Mechanism of Non-Absorption of Rifaximin

The chemical structure of rifaximin incorporates a pyridomidazole functional group that gives it almost zero solubility in lipids and water. This physical-chemical characteristic absolutely prevents its systemic absorption through the gastric and colonic gastrointestinal epithelium (its systemic bioavailability is less than 0.4%). The drug remains concentrated exclusively in the intestinal lumen, acting as a powerful broad-spectrum bactericide on ammonia-producing aerobic and anaerobic bacteria in the colon, without inducing systemic bacterial resistance or general metabolic adverse effects.

Pharmacokinetics

• UDCA: It is rapidly absorbed in the small intestine by passive and active transport, undergoes a first-pass hepatic clearance of 60% - 80% and is conjugated with glycine or taurine to be excreted directly into the bile. Its elimination is complete fecal.
• Pancreatin: Does not undergo any appreciable systemic absorption. The enzymes are degraded and digested by physiological enzymatic autolysis along the gastrointestinal tract.
• Rifaximin: Not absorbed. It is eliminated intact and unaltered in 99.6% of feces.

Indicators and dose

Approved indications

• Ursodeoxycholic acid: Treatment of primary biliary cholangitis (PBC) in the absence of active decompensated cirrhosis; dissolution of radiolucent cholesterol gallstones in patients with a functioning gallbladder.
• Pancreatin (Enzymes): Treatment of exocrine pancreatic insufficiency (EPI) secondary to cystic fibrosis, chronic recurrent pancreatitis, total or partial pancreatectomy, or gastric resection.
• Rifaximin: Reduction of recurrence of episodes of overt hepatic encephalopathy in adults; treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) and luminal bacterial infections (traveler's diarrhea due to non-invasive strains of E. coli).

Dosage and Clinical Adjustment

Ursodeoxycholic Acid (Adults with PBC):

• 13 mg to 15 mg per kilogram of body weight per day (mg/kg/day), divided into two or three daily oral doses, administered for life to effectively delay the progression to terminal biliary cirrhosis.

Pancreatin (Pancreatic insufficiency):

• Dose individualized by body weight and dietary fat content of the diet. Standard starting range: 25,000 to 50,000 lipase units orally for each main meal, and 10,000 to 25,000 units with light snacks.
• The capsules should be swallowed whole during meals. Do not chew or crush the contents (the microspheres have an acid-resistant enteric coating that prevents their inactivation by gastric acid in the stomach; they are only activated at pH > 5.5 in the duodenum).

Rifaximin (Adults):

• Prevention of hepatic encephalopathy: 550 mg orally twice a day on an empty stomach on a chronic basis, usually combined with supportive lactulose.
• IBS-D: 550 mg orally three times a day for 14 days.

Renal/Hepatic Adjustment: No modifications are required in mild to severe organic failures for any of the three drugs described in this section.

Security

Contraindications

• UDCA: Calcified gallstones opaque to X-rays. Untreated acute cholecystitis. Complete obstruction of the intra- or extrahepatic bile ducts. Non-functioning gallbladder.
• Pancreatin: Documented hypersensitivity to proteins of porcine origin. Initial phases of severe decompensated acute pancreatitis (to avoid digestive overstimulation).
• Rifaximin: Cases of active intestinal obstruction. Invasive diarrhea accompanied by high fever and bloody stools (severe dysentery).

Adverse effects (ADRs)

• UDCA: Soft stools, mild colonic diarrhea (due to increased salts in the colon), temporary pain in the right hypochondrium.
• Pancreatin: Mild dyspepsia-type abdominal pain, perianal irritation in children due to high doses. Severe fibrosing colonopathy: Painful stenosis of the cecum and ascending colon, described mainly in children with cystic fibrosis receiving extremely high chronic doses of concentrated enzyme preparations.
• Rifaximin: Excellent symptomatic tolerance due to zero absorption. Dizziness, occasional flatulence, mild abdominal pain, rectal tenesmus.

Safety in Pregnancy and Breastfeeding

UDCA: Widely safe and considered the choice for the treatment and control of intrahepatic cholestasis of pregnancy (ICP) in the second and third trimesters of pregnancy, improving unbearable maternal pruritus and substantially reducing perinatal fetal mortality and morbidity.

Pancreatin: Compatible with pregnancy and lactation. As it acts purely topically luminally and is not absorbed systemically, there is no risk of systemic exposure of the embryo, fetus or infant.

Rifaximin: Preferred to be avoided as a precaution. Although it is not absorbed, specific clinical studies in pregnant women remain insufficient to completely rule out any indirect risk.