Hepatoprotectors
Hepatoprotectors
2. The drugs containing natural or semisynthetic flavonoids of other plants: Chophytol, Catergen (Cianidanol), Liv.52 (Hepaliv).
3. Organic drugs of animal origin: Sirepar, Hepatosan.
4. The drugs containing essential phospholipids: Essentiale, Phosphogliv, Essliver, эплир.
5. The drugs of different groups: Бемитил, Adamethionin (Heptral), Lipoic acid (Thioctacid), Hepa-Merz (Ornithine), ursodeoxycholic acid (Ursofalk), non-steroid anabolics (Methyluracil, Pentoxyl, Sodium nucleinate).
Essential phospholipids (EPL)
Pharmacodynamics. The EPL drugs provide biological membranes of hepatocytes with phospholipids. The EPL substance is a highly-purified extract out of soya beans that mostly contains the molecules of phosphatidylcholine (PC) with high concentration of polyunsaturated fatty acids. The main active ingredient of EPL is 1,2 dilinoleophosphatidylcholine the synthesis of which is impossible by the human body. The presence of 2 essential fatty acids condition the superiority of this special form of phospholipids over endogenous phospholipids. Membrane-stabilizing and hepatoprotecting actions of EPL is achieved by way of direct embedding of EPL molecules into the phospholipid structure of the damaged hepatocytes replacing the defects and restoring the barrier function of the lipid layer of membranes. Unsaturated fatty acids of phospholipids promote the increasing of activity and fluidity of membranes, decrease the thickness of phospholipid structures and normalize penetrability.
Exogenous EPL promote activation of phospholipid-dependent enzymes located in the membrane as well as of transport proteins that in its turn has a supportive effect on metabolic processes in the liver cells, contributes to its detoxifying and excretory capacity.
Through this mechanism EPL normalize liver enzymes in the blood that is increased when there’s cytolytic syndrome. They induce the synthetic function of the hepatocytes directed at maintaining of the level of plasma proteins in case of hepatocellular insufficiency syndrome. They contribute to the regeneration of liver cells (hepatocytes, cholangiocytes, etc.), activate transportation of liver lipids (cholesterol, triglyceride, phospholipids) in the structure of lipoproteins synthesized in the liver. EPL have a positive effect on energy metabolism by acting on the processes of glycogenolysis, glycogen synthesis, gluconeogenesis, fatty acid oxidation. They have a choleretic action, activating the oxidation of cholesterol to bile acids by stabilizing the physicochemical properties of the bile increasing the amount of secreted bile. They slow down the collagen synthesis, increase the activity of collagenase, which leads to an increase in an antifibrotic effect.
Pharmacokinetics. Most EPL drugs also contain some water and fat-soluble vitamins (B1, B2, B6, B12, tocopherol and nicotinamide). That’s why the conduction of pharmacokinetic studies of EPL drugs is not possible.
Indications. EPL are used with 3 main purposes:
- In case of liver diseases and its toxic damages;
- In case internal organs pathology complicated by a liver damage;
- As a method of "medicamentous cover" while using the drugs causing liver damage (tetracycline, rifampicin, paracetamol, indomethacin, etc.).
In hepatology EPL are prescribed for chronic hepatitis, cirrhosis, fatty degeneration, hepatic coma. They are also used for radiation syndrome and toxicosis during pregnancy, to prevent a recurrence of gallstone disease after removal of stones, for preoperative and postoperative treatment of patients, especially in cases of surgical interventions in the liver and biliary tract. At the same time, when using EPL for active hepatitis on needs to be cautious because in some cases they can lead to increased inflammatory activity and cholestasis.
Contraindications. High sensitivity to EP drugs.
Adverse side effects. The increase in manifestations of intrahepatic cholestasis syndrome, the presence of extrahepatic cholestasis associated with concrements in the biliary tract, pancreatitis, cholangitis. Diarrhea, abdominal discomfort caused by the choleretic effect of EPL.
EPL drugs
The prototype of the compounds containing EPL substance is a drug Essentiale forte, which is composed of EPL, unsaturated fatty acids and vitamins. Not so long ago essentiale H appeared on the market and it contains only EPL substance of high purity. Essliver forte is a drug containing EPL, thiamine mononitrate, riboflavin, pyridoxine hydrochloride, Cyanocobalamin, nicotinamide, tocopherol acetate. The use of drugs without the addition of vitamins is preferable.
Dosing regimen. It is advisable to start EPL therapy with intravenous administration. 0.25 - 0.5 g within 10 days. Then 2 capsules 3 times / day during the meal. The course is at least 3 months.
The
drugs containing natural or semisynthetic flavonoids thistle
Hepabene, Legalon, Carsil, Hepatofalk planta, Silibor contain an extract (or a mixture of flavonoids) out of Saint-Mary-thistle, the main component of which is silymarin, which consists of 3 main isomeric compounds - silibinin, silychristin and silydianin (in legalon, for example, ratio of 3: 1: 1). All isomers have phenylchroman structure (flavolignans). Silibinin is a major component not only in terms of the content, but also in terms of the clinical effect. The main effects of silymarin (silibinin) are membrane-protecting, antioxidant and metabolic. Silibinin stabilizes the membranes of liver cells. Furthermore, silibinin blocks phosphodiesterase that promotes the delayed disintegration of cAMP, and thus stimulates a decrease of intracellular calcium concentration in hepatocytes and reduces the calcium-dependent activation of phospholipases. Antioxidant and metabolic properties of silibinin also play an important role in stabilizing the membrane.
Silibinin is capable of blocking the corresponding places of connection between a number of toxic substances and their transport systems. Metabolic effects of silibinin are to stimulate protein synthesis and accelerate regeneration of damaged hepatocytes. Silibinin stimulates RNA polymerase I in the cell nucleus and activates transcription and the rate of RNA synthesis, and, consequently, protein in liver cells. In case of liver cirrhosis fibrosis of the organ is slowing down under the influence of the drug.
The
derivatives of silymarin are advisable to use for the patients with
liver disease with its clinical and biochemical signs of activity.
Caution should be taken in patients with cholestasis, since it’s
been proved that under the influence of drugs cholestasis can be
enhanced. Carsil and Legalon are used for acute and chronic
hepatitis, liver cirrhosis, toxic-metabolic liver damage, including
the damage with xenobiotics. The peculiar property of Hepatofalk
planta
is that its composition includes extracts from celandine and Javanese
turmeric along with an extract of milk thistle. That is why along
with hepatoprotective effect the drug has also choleretic,
antispasmodic and anti-inflammatory effects. It reduces the
saturation of bile with cholesterol, has anti-bacterial properties.
It is used for acute and chronic hepatitis, fatty hepatosis,
cirrhosis of the liver.
Hepabene
has similar properties. It consists of extracts of milk thistle and
fumitory. The latter has an antispasmodic action. The drug is used
for the patients with chronic hepatitis and liver cirrhosis, fatty
degeneration of the organ, toxic-metabolic organ damage, including
the one with xenobiotics.
Chophytol
is a drug one ampoule of which contains 0.1 g of purified extract of
artichoke leaves in isotonic solution. The main hepatoprotective and
choleretic effect is possible due to the presence of a phenolic
compound cynarin combined with phenolic acids (caffeic, chlorogenic
acids etc.). In addition, it contains carotene, vitamin C, B1, B2,
inulin. It affect the functional activity of the liver cells,
stimulates the production of enzymes. This explains the effect of the
drug on lipid metabolism, increased antitoxic function of the liver.
Chophytol reduces the level of cholesterol in the blood during the
initial hypercholesterolemia, has choleretic effect due to moderate
and weak cholekinetic effect. It is used for toxic hepatitis, liver
cirrhosis. The drug has low toxicity.
Pharmacokinetics. The drug is slowly and insignificantly absorbed from the gastrointestinal tract. Half-life period - 2.2 hours. It doesn’t accumulate in the body. It participates in the entero-hepatic circulation. Biotransformed in the liver by conjugation. T1 / 2 - 6 hours. It is excreted mainly with bile in the form of glucuronides and sulphites.
Undesirable side effects are rare and in the form of allergic reactions, diarrhea.
Dosing regimen. The drugs Llegalon, Carsil are prescribed individually. In severe cases – 140 mg 3 times a day. In mild cases and for maintenance therapy – 70 mg 3 times. Solid dosage forms should be taken without chewing, with a small amount of water.
The drugs containing natural or semisynthetic flavonoids of other plants
Liv.52
(Hepaliv) contains a number of medicinal plants commonly used in
traditional Indian medicine. It is believed that Liv-52 protects the
liver parenchyma from toxic agents. It acts as a therapeutic or
prophylactic agent. It enhances the intracellular metabolism and
stimulates regeneration. At the same time it’s been proved that the
use of the drug in acute liver pathology may exacerbate the severity
of cytolytic and mesenchymal-inflammatory syndromes. That is why this
drug can be recommended at the moment when the severity of the
inflammatory syndrome in liver is minimal and synthetic organ failure
phenomena are prevailing.
Dosing regimen. With therapeutic purpose it is prescribed for adults 2-3 tablets 3 times/day. For prevention – 2 tablets 2 times/day.
Tycveol is a complex of biologically active substances derived from pumpkin seeds. The hepatoprotective effect of Tykveol is determined by its membrane stabilizing properties and appears to slow down the development of hepatocyte membrane damage and accelerate their recovery. In addition, the drug reduces inflammation and slows down the development of connective tissue and accelerates the regeneration of damaged liver parenchyma. Tycveol has a choleretic effect, it normalizes the chemical composition of bile, reduces the risk of gallstones and exerts a positive effect on its course. Tycveol is used for chronic liver diseases of different etiologies: chronic liver disease of various etiologies (hepatitis, cirrhosis), holecystohologitis and biliary dyskinesia, postoperative cholecystectomy, for the prevention of gallstones.
The
drugs
of
other
groups
S-adenosyl-L-methionine (Heptral) plays a central role in the synthesis and exchange of glutathione and taurine, in conjugation of bile acids with increasing hydrophilicity, in detoxification of bile acid and many xenobiotics, in protein synthesis in the liver. At the use of Adamethionine the elimination of free radicals and other toxic metabolites out of the hepatocytes increases. The drug has also antineurotoxic and antidepressant action. Adamethionine is quite effective in the pathology of the liver accompanied by hepatic encephalopathy. However it should be noted that the maximum expression of hepatoprotective effect is only achieved when the drug is administered parenterally. Adamethionine influences predominantly on the manifestations of toxemia and affects cytolysis and cholestasis but to a much lesser extent. The drug is taken between meals. It is used for acute and chronic hepatitis, cirrhosis of the liver.
Pharmacokinetics. The bioavailability when taken P/O – 5%, when administered I/M – 95%. Binding to plasma proteins is insignificant, penetrates through BBB. The time to reach maximum concentration – 2 - 6 hours. Metabolized in the liver. Т1/2 - 1.5 hours. Excreted mainly by the kidneys.
Adverse side effects. Insignificant. Mild epigastric discomfort is possible. I and II trimesters of pregnancy. Due to the insufficient number of clinical observations it should be used with caution in pediatric practice.
Dosing regimens. At the first stage the drug (Heptral) is administered intravenously (bolus or slow infusion) with a dose of 800 mg / day once for 14 days. Intraintestinal administration is possible. Then P/O – 800 mg x 2 times / day for 2-4 weeks. Remove the tablet from the blister pack immediately before use. Taken between meals; avoid taking at bedtime.
L-ornithine-L-aspartate (Hepa-Merz) - a relatively new drug for the treatment of diseases of the liver, regulates metabolism in the liver cells. In the intestine, the drug dissociates into its components - amino acids ornithine and aspartate, which participate in the further biochemical processes:
Ornithine aspartate intensifies ammonia metabolism both in liver and in brain. It has a positive impact on hyperammonemia and encephalopathy dynamics in patients with cirrhosis of the liver. It promotes the normalization of acid-base balance of the body, the development of insulin and growth hormone. It is used for steatosis, hepatitis, cirrhosis, liver damage as a result of alcohol and drug abuse, to treat disturbances of the brain resulting from disorders of the liver. The duration of treatment is determined by the dynamics of the concentration of ammonia in the blood and by the state of a patient. The course of treatment may be repeated every 2-3 months.
Ursodeoxycholic acid (UDCA) - hydrophilic, non-toxic, tertiary bile acid. Its content in the natural pool of bile acids is only 4%. The use of UDCA reduces the enterohepatic circulation of hydrophobic bile acids having hepatotoxic effect, thereby preventing their toxic effect on the membrane of hepatocytes and biliary epithelium, inhibits immunoglobulin production, normalizes HLA-DR antigens on the surface of cell membranes, thus reducing their autoimmunity, reduces cholestasis-mediated immunosuppression. The positive choleretic influence of UDCA is that due to the increased passage of bile it causes increased excretion of toxic substances out of the liver. UDCA has an antioxidant effect, reducing the oxidative activation of Kupffer cells by hydrophobic bile acids. At present, the administration of UDCA is justified in diseases of the liver, accompanied or caused by cholestasis, regardless of etiology. It is used in patients with acute and chronic hepatitis (including autoimmune), toxic (including alcohol) liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis (before severe cirrhotic transformation of the liver), hepatopathies of the pregnant.
Pharmacokinetics. After the oral administration, UDCA is absorbed in the small intestine by passive diffusion, and in ileum – by way of active transport. C max in plasma is reached in 30-60 min. after administration. At the regular use, UDCA becomes the primary bile acid in the blood plasma. Binding to plasma proteins - 96-99%. The maximum concentration in bile is achieved when receiving a dose of 10-14 mg / kg of body weight. There’s no increase of concentration with subsequent increase of the dose. About 50-70% of the dose is excreted with bile.
Adverse side effects. UDCA – a safe drug. Diarrhea, transient increase in liver transaminases and transient loose stools, itching, and allergic reactions.
Contraindications. Acute inflammatory diseases of the gallbladder and biliary tract. Hypersensitivity to the drug. The prescription is undesirable during pregnancy.
Dosing regimens. UDCA drugs (ursosan, ursofalk) are administered orally. For the treatment of gallstone disease and reflux gastritis – 1 time / day before sleep. For liver disease, for the dissolution of gallstones – 10 to 12-15 mg / kg of body weight. The course of treatment is long and continuous from several months to several years. For biliary reflux gastritis - 250 mg / day. The course 10 - 14 days. The bioavailability of UDCA decreases while taking cholestyramine or aluminium-containing antacids.
Alpha-lipoic acid (lipamid, Thioctacid) is a coenzyme participating in the oxidative decarboxylation of pyruvic acid and alpha-keto acids, plays an important role in the bioenergetics of liver cells, participates in the regulation of carbohydrate, protein and lipid metabolism, has a lipotropic effect. It participates in multienzymatic mitochondrial complexes as a coenzyme.
The drug also has an antioxidant activity. Additional administration of alpha-lipoic acid has a good effect in the pathology associated with oxidative stress (reperfusion organ damage, diabetes, cataracts, radiation damage). Alpha-lipoic acid is used in viral hepatitis A, fat hepatosis, chronic hepatitis, liver cirrhosis.
Table 1*Compatability of some hepatoprotectors for liver diseases
