Pharmacological properties
Pharmacodynamics. Ursodeoxycholic acid (UDCA) is a 7β-epimer of chenodeoxycholic acid and bile acid, which is physiologically present in human bile in insignificant concentrations compared to the total amount of bile acids.
UDCA inhibits hepatic cholesterol synthesis and secretion, as well as intestinal cholesterol absorption. It probably has a weak inhibitory effect on the synthesis and biliary secretion of endogenous bile acids and does not affect the secretion of phospholipids into the bile.
With continuous administration of the drug, the concentration of UDCA in bile reaches a maximum value after about 3 weeks. Despite its insolubility in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxybile acids. In addition to solubilizing cholesterol in micelles, UDCA has a unique effect that causes the dissolution of cholesterol in the form of liquid crystals in an aqueous medium. Thus, despite the fact that the administration of high doses (for example, 15-18 mg / kg / day) does not lead to a concentration of UDCA exceeding 60% of the total bile acid pool, bile enriched with UDCA effectively dissolves cholesterol. The overall effect of UDCA is to increase the concentration of bile, at which its saturation with cholesterol occurs.
The various mechanisms of action of UDCA are aimed at reducing the level of calculi-forming cholesterol secreted into bile, as well as solubilizing it, which contributes to the dissolution of cholesterol gallstones.
After discontinuation of UDCA, bile acid concentration in bile decreases exponentially, falling to approximately 5-10% of its normal level after approximately 1 week.
Pharmacokinetics. About 90% of a therapeutic dose of UDCA is absorbed in the small intestine after oral administration. After absorption, UDCA enters the liver via the portal vein and undergoes primary metabolism (i.e., there is a pronounced first-pass effect), where it is conjugated with glycine or taurine and then secreted into the hepatic bile ducts. UDCA in bile is concentrated in the gallbladder and released into the duodenum from the gallbladder through the common duct due to contraction of the gallbladder, which is a physiological response to food. Only trace amounts of UDCA appear in the systemic circulation, a very small amount of it is excreted in the urine. The area of therapeutic effects of the drug is in the liver, bile and intestinal lumen.
Apart from conjugation, UDCA is not metabolized by the liver or intestinal mucosa. A small amount of the drug is subject to bacterial degradation with each cycle of hepatic circulation. UDCA can be either oxidized or reduced at the 7-carbon, yielding 7-ketolithocholic acid (7-CLH) or lithocholic acid (LHC), respectively. In addition, bacterially catalyzed deconjugation of glyco- and tauroursodeoxycholic acid occurs in the small intestine. Free UDCA, 7-CLH, and LHC are insoluble in water, and large amounts of these compounds are excreted from the distal intestine in the feces. Reabsorbed free UDCA is reduced by the liver. 80% of LHC formed in the small intestine is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to relatively insoluble lithocholyl conjugates, which are excreted in the bile and dissolved in the feces. Absorbed 7-CHL is stereospecifically cleaved in the liver to chenodiol.
LHC is formed by 7-dehydroxylation of dihydroxybile acids (UDCA and chenodiol) in the intestinal lumen. The 7-dehydroxylation reaction is alpha-specific, i.e. chenodiol is more efficiently 7-dehydroxylated than UDCA, and for equimolar doses of UDCA and chenodiol, the levels of LHC present in bile do not change. During experiments on animals, it was recorded that the accumulation of LHC leads to liver damage due to insufficient activity of LHC sulfation. Humans have the ability to sulfate LHC. Liver damage was noted in some patients during studies, but it was not associated with UDCA therapy. This is explained by the fact that some people may have a reduced ability to sulfate, but this phenomenon has not been studied.
Indication
Urson is prescribed to patients with radiopaque, non-calcified gallstones 20 mm in greatest diameter for whom elective cholecystectomy may be performed, including patients at high surgical risk due to systemic disease, elderly patients, individuals with individual intolerance to general anesthesia, or patients who refuse surgery.
Urson is prescribed to prevent the formation of gallstones in obese patients who plan to lose weight quickly.
Application
UDCA should be used under the supervision of a physician.
The capsules should be swallowed whole with liquid. It is necessary to observe regularity of administration.
For patients whose body weight is less than 47 kg or who have difficulty swallowing capsules, it is recommended to use the drug in another dosage form (e.g. suspension).
Control ultrasound of the gallbladder should be performed every 6 months during the first year of therapy with the drug. If the gallstones dissolve, the drug should be continued and ultrasound should be performed every 1-3 months. In most patients who ultimately had complete dissolution of the stones, partial or complete dissolution of the stones was noted at the first assessment of treatment. If partial dissolution of the stones is not observed after 12 months of therapy with the drug Urson, the likelihood of success is significantly reduced.
Prevention of gallstone formation. The recommended dose for the prevention of gallstones in patients planning rapid weight loss is 600 mg/day (300 mg twice daily).
Contraindication
Patients with calcified cholesterol or radiopaque stones.
Patients with urgent indications for cholecystectomy, including non-remitting acute cholecystitis, cholangitis, biliary obstruction, cholelithiasis pancreatitis, or patients with biliary-enteric fistulas.
Allergy to bile acids.
Side effects
During the studies, the nature and frequency of adverse reactions were the same in all groups. The most frequently observed adverse reactions and conditions are listed below:
General disorders: flu-like symptoms, allergies.
Gastrointestinal tract: abdominal pain, dyspepsia, constipation, diarrhea, nausea, vomiting, cholecystitis.
Respiratory system: bronchitis, cough, pharyngitis, upper respiratory tract infections.
Musculoskeletal system: arthralgia, arthritis, back pain.
From the nervous system: dizziness, headache.
Skin and Appendages: hair loss.
From the genitourinary system: urinary tract infections.
Hypersensitivity reactions: very rarely, allergic reactions are possible, including rash, urticaria.
Special instructions
Dissolution of gallstones with urson requires long-term therapy. Complete dissolution does not occur in all patients, and recurrence of stone formation within 5 years is observed in 50% of patients treated with UDCA. The conditions of UDCA therapy must be carefully followed, and alternative treatment methods should also be considered. The safety of urson use for more than 24 months has not been established.
The ability to monitor bile composition to verify the reduction of cholesterol content in bile is an important element of a favorable prognosis of treatment outcomes.
Patients with frequent biliary colic, biliary tract infections, severe pancreatic disorders, or persons with intestinal diseases that may affect the gastrohepatic circulation of bile acids (jejunoileal resection or stoma, regional ileitis) should use the drug with caution.
Patients taking ursone to dissolve gallstones should have an ultrasound or cholecystography every 6 months to check the effectiveness of the drug. One indicator of progressive treatment may be monitoring the composition of bile to monitor the decrease in cholesterol content.
Women who use the drug to dissolve gallstones should use an effective non-hormonal method of contraception, as hormonal contraceptives may increase the formation of gallstones.
Ultrasound or cholecystography is recommended to be repeated every 6 months in patients who use ursone to dissolve gallstones.
During the first 3 months of treatment, the doctor should monitor liver function by taking samples for AST, ALT and GGT every 4 weeks and every 3 months during further treatment. Control studies make it possible to determine whether the patient's body is responding to the treatment of primary biliary cirrhosis, and such monitoring also allows for early detection of potential deterioration in liver function.
Dissolution of cholesterol gallstones. For a correct assessment of the therapeutic effect and for timely detection of calcified gallstones, their size and condition, it is necessary to perform visualization of the gallbladder (oral cholecystography): general image and occlusion in the patient's standing, supine (ultrasound) positions 6-10 months after the start of treatment, taking into account the size of the stones.
It is not advisable to use UDCA if the gallbladder cannot be visualized by X-ray due to calcified gallstones, impaired gallbladder contractions, or frequent biliary colic.
Use in the elderly. In clinical studies, approximately 4% of patients were 65 years of age or older (approximately 3% were 75 years of age or older). No age-related differences in safety and efficacy were observed. Other reported clinical studies have not shown any differences in efficacy between elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly patients taking ursone cannot be ruled out. Therefore, individualized dosage adjustment is recommended for patients in this age group.
UDCA should not be used during pregnancy unless clearly necessary. Ursone should only be used by women of childbearing potential if they are using proven contraception. Non-hormonal contraceptives or low-estrogen oral contraceptives are recommended. If patients are taking UDCA as a means of dissolving gallstones, only effective non-hormonal contraceptives should be used, as hormonal contraceptives may promote gallstone formation. Pregnancy should be ruled out before starting treatment.
There is no information on the penetration of ursone into breast milk. Therefore, the drug should not be used during breastfeeding. If treatment with UDCA is necessary, breastfeeding should be discontinued.
Children: There is insufficient experience with the use of the drug in children.
Ability to influence the reaction speed when driving vehicles or working with other mechanisms. No effect on the ability to drive vehicles or work with complex mechanisms was observed.
Interactions
Bile acid sequestrants, such as cholestyramine and colestipol, may interfere with the action of UDCA, reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may therefore reduce the absorption of UDCA. Estrogens, oral contraceptives, and clofibrate (as well as other lipid-lowering drugs) increase hepatic HCL secretion and may reduce the efficacy of UDCA.
Urson may increase the absorption of cyclosporine in the intestine. Therefore, in patients taking cyclosporine, it is necessary to monitor the concentration of this substance in the blood and, if necessary, change the dose.
In some cases, UDCA may reduce the absorption of ciprofloxacin.
A decrease in the maximum plasma concentration (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine was observed when it was used simultaneously with UDCA. When interacting with dapsone, a decrease in the severity of the therapeutic effect of UDCA was noted.
These observations and in vitro studies suggest the potential of UDCA to induce P450 3A enzymes. However, controlled clinical studies have shown that UDCA does not have a significant inductive effect on P450 3A enzymes.
Estrogen hormones and agents that lower blood cholesterol levels, such as clofibrate, may promote gallstone formation, exerting an effect opposite to that of UDCA, which is used to dissolve gallstones.
Overdose
In case of overdose, diarrhea is possible. Other symptoms of overdose are unlikely, since the absorption of UDCA decreases with increasing dose, so most of its amount is excreted in the feces.
If diarrhea occurs, the dose should be reduced, and if diarrhea is persistent, therapy should be discontinued.
No specific measures are necessary. Treatment for diarrhea is symptomatic, aimed at restoring fluid and electrolyte balance.
There are known cases of UDCA overdose when using the drug at a dose of up to 4 g/day, but this dose did not have significant consequences.
If UDCA has been accidentally taken in high doses, it is recommended to take the usual measures as in case of intoxication, or to prescribe cholestyramine to bind bile acids.
Additional information on special patient groups: Long-term high-dose UDCA therapy (28-30 mg/kg/day) in patients with primary sclerosing cholangitis (off-label use) was associated with a higher incidence of serious adverse events.
Storage conditions
At a temperature not exceeding 25 °C.
