Pancreatic Enzyme Drugs

Syndrome of exocrine pancreatic insufficiency (EPI) is due to a decrease in the mass of its functioning exocrine parenchyma as a result of atrophy, fibrosis, neoplasia, or a violation of the outflow of pancreatic secretion into the duodenum due to the block of the excretory ducts of pancreas by a concrement, a tumor, or thick and viscous secretion. In addition, there is the so-called secondary pancreatic insufficiency, when pancreatic enzymes are not activated, or inactivated in the intestine. The development of atrophic changes in the mucous membrane of the proximal small intestine is important, when the number of I-cells and S-cells secreting cholecystokinin and secretin decreases, respectively. A deficiency of endogenous secretin causes a violation of a number of functions of the digestive organs: the pressure in the duodenum and pancreatic ducts increases, spasm of the Oddi sphincter is noted, the volume of pancreatic juice and bicarbonates is reduced. As a result, the secretion of the liquid part of pancreatic juice decreases, which leads to its thickening and increase in its protein concentration, and consequently, to an increase in viscosity and a decrease in the rate of secretion outflow.

The pancreas has a huge reserve of enzyme secretion, since under physiological conditions it produces about two liters of pancreatic juice per day, containing 10 times more enzymes and zymogen, than is required for normal digestion of food (physiological hypersecretion). This means that for the development of malabsorption syndrome, the secretory ability should decrease significantly, to about 5–10% of the physiological hypersecretion, or, in other words, from the “norm”.

Multienzyme preparations are combined multicomponent drugs, mainly of animal origin, the main active substrate of which is pancreatin in pure form or in combination with additional components (bile acids, hemicellulase, simethicone, adsorbents, etc.)

Multienzyme preparations, depending on the combination of their constituent components, can be divided into several groups (table):

1. Extracts of the gastric mucosa, the main active ingredient of which is pepsin (abomin, pepsidil, acidinpepsin).
2. Pancreatic enzymes, which include amylase, lipase and trypsin (pancreatin, pancytrate, mezim-forte, creon, licrease, etc.).
3. Combined medications containing, in addition to pancreatin, components of bile, hemicellulase, simethicone, etc. (festal, digestal, pansteel, enzyme, pancreoflat, etc.).
4. Combined enzymes containing animal enzymes (Pancreatin) in combination with plant enzymes, vitamins (Wobenzym), Combicin (Pancreatin and rice fungus extract).
5. Actually plant enzymes represented by papain, fungal amylase, protease, lipase, and other enzymes (pepfiz, oraz).
6. Enzymes containing lactase (lactrase, tilactase).

The use of the first group of enzymes in patients with pancreatitis is indicated only with a combination of severe exocrine pancreatic insufficiency and atrophic gastritis. The drugs of 2-4 groups contain animal pancreatin, but due to their different composition and, therefore, pharmacological effect, they are not interchangeable and have clear indications for use.

The most universal drugs that normalize digestion in maldigestion and malabsorption syndromes are pancreatin medications, which do not affect the function of the stomach, liver, and motility of the biliary system and intestines. These enzymes provide a sufficient spectrum of digestive activity and contribute to the relief of such clinical signs as nausea, rumbling in the abdomen, flatulence, steato, creato and amilorrhea. The amylase entering the polyenzyme complex breaks down predominantly extracellular polysaccharides to simple sugars, sucrose and maltose, practically without participating in the hydrolysis of plant fiber. Proteases in pancreatin drugs are mainly represented by chymotrypsin and trypsin. Lipase is involved in the hydrolysis of neutral fat.

Along with pancreatin, combined medications contain bile acids, hemicellulase, simethicone, vegetable choleretic (turmeric), etc. The introduction of bile acids into the preparation significantly changes its effect on the function of the digestive glands and the motility of the gastrointestinal tract. Pancreatic secretion increases choleresis, stimulates intestinal motility and gall bladder. Under conditions of microbial contamination of the intestine, they are deconjugated, which in some cases contributes to the activation of cAMP markers with subsequent development of osmotic and secretory diarrhea. Enzyme medications containing bile acids are contraindicated in patients with edematous and painful forms of chronic pancreatitis, because they increase the secretion of the pancreas, stimulate intestinal motility and gall bladder motility, increase intraintestinal osmotic pressure and, consequently, abdominal pain syndrome.

Indications for enzyme replacement therapy of chronic pancreatitis with exocrine insufficiency:

1. steatorrhea with the loss of feces more than 15 g of fat per day;
2. progressive trophological failure;
3. persistent diarrhea syndrome and dyspeptic complaints.

Pharmacological aspects of multienzyme replacement therapy

The main purpose of pancreatic enzyme replacement therapy is to ensure sufficient lipase activity in the duodenum. It is known that the effect of hydrochloric acid on pancreatic enzymes leads to the destruction of up to 90% of their number, therefore, the creation of medicinal forms of multienzyme preparations in an acid-resistant membrane helped to overcome the acidic gastric barrier. The use of the drug with such coating increases the absorption of fat by an average of 20% compared to a comparable dose of pancreatin without such coating.

If the postprandial pH in the stomach depends on both the individual characteristics of secretion and the amount of food and the time it stays in the stomach, then the intraduodenal pH depends on the residual secretion of pancreatic bicarbonates, the secretion of bicarbonates by the small intestine, on the dilution volume, as well as on the amount of salt and bile acids. Therefore, when using pancreatic enzymes with an acid-resistant membrane, the intragastric pH should not exceed 5, since in this case the enzymes will be released from the enteric membrane in the stomach. If this happens, then part of the enzymes in patients with impaired motor function will be irreversibly destroyed during reacidification.

• Most enzyme preparations come in the form of dragees or tablets in enteric-soluble membranes, which protects the enzymes from the release in the stomach and the destruction by hydrochloric acid of gastric juice. The size of most tablets or pills is 5 mm or more. Nevertheless, it is known that, simultaneously with food, solid particles with a diameter of no more than 2 mm can be evacuated from the stomach at an optimal size of 1.4 mm [33]. Larger particles, in particular enzyme preparations in tablets or dragees, are evacuated in the interdigestive period, when the food chyme is absent in the duodenum. As a result, drugs are not mixed with food and are not actively involved in the processes of digestion. If the tablet or dragee is in the stomach for a long time, the enteric coating is destroyed, and the enzymes inside are inactivated.

• For the correction of steatorrhea, it is necessary to provide about 28 000 IU of lipase within 4 hours of postprandial period. Currently, there is a large number of different multienzyme preparations, the content of lipase in which varies greatly (within 0-25000). Accordingly, for the correction of steatorrhea, it is necessary to use drugs only with a high content of lipase.

• To ensure the rapid and homogeneous mixing of enzymes with the food chyme, to prevent intragastric inactivation and adequate passage of the stomach into the duodenum, pancreatin enzyme medications of the new generation were created in the form of microtablets (creon, licrease) the diameter of which does not exceed 2 mm. The drugs are coated with enteric coatings and enclosed in gelatin capsules. When ingested, gelatin capsules dissolve quickly, microspheres or microtablets get mixed with food and gradually enter the duodenum. When the pH of the duodenal content is above 5.5, the membranes dissolve and the enzymes begin to act on a large surface. At the same time, physiological processes of digestion are practically reproduced, when pancreatic juice is excreted in portions in response to the periodic intake of food from the stomach. The drug Creon is also characterized by an optimal ratio of lipase and colipase activity, a high content of carboxylesterolipase and phospholipase A2 for the most efficient breakdown of fats.

• Thus, microencapsulated and microtabletted medications can be attributed to the most modern multienzyme drugs for enzyme replacement therapy, including those that meet present-day requirements for these drugs, formulated on the basis of the experimental, theoretical, biochemical and clinical works described above:

1. medications should not be of plant origin, but of animal origin;
2. they should consist of a sufficient amount of enzymes (lipase content per meal up to 30,000 IU);
3. the presence of an enteric coating;
4. even and quick mixing with food;
5. simultaneous passage of enzymes with food through the pyloric part in duodenum;
6. rapid release of enzymes in the upper portions of small intestine;
7. lack of bile acids.
8. safety, no toxicity.

Therefore, the first drugs of choice for chronic pancreatitis with exocrine insufficiency are creon and pancytrate. The widely used mezim-forte in doses of 3-6 tablets per day can be used only for the correction of pancreatic dysfunction that occurs when there are errors in nutrition. While creon with an activity of 25 000 IU of lipase can completely replace the exocrine function of the pancreas [10]. The drug, which fully satisfies the above requirements and has been used recently, is a highly active multienzyme preparation in the form of minimicrospheres (Creon 10 000 and Creon 25 000), coated with an enteric coating. This drug is comparable to its predecessor Creon 8000 and similar preparations from other manufacturers in that the average size of minimicrospheres is reduced to 1 mm.