Digestive enzymes are widely used in various gastroenterological pathologies. Enzymes are actively used in various diseases of the stomach, small and large intestine, biliary tract and pancreas. Indications for prescribing enzyme therapy are disorders of endogenous enzyme secretion, disorders of absorption of nutrients and gastrointestinal motility. The global pharmaceutical industry now produces a large number of enzyme preparations (Digestal, Creon, Mesim-Forte, etc.), which differ from each other both by the dosage of digestive enzymes they contain and by various additives (see Table). Digestive enzymes are available in different forms: as tablets, powders or capsules containing microgranules with enterosolubilic coating. All enzyme preparations differ in their composition: containing pancreatin (pancreatic extract, usually of porcine origin) or digestive enzymes, of plant origin, gastric mucosa extract. In addition to enzymes, the drug may contain components of bile, gastric mucosa or adsorbents (simethicone or dimethicone).
The choice of a drug for the treatment of a patient with gastroenterological pathology should be based on the following indicators:
– absolute and relative content of enzymes in the drug (high content of proteases is indicated in patients with decreased gastric secretion and painful form of chronic pancreatitis; increased lipase activity is necessary for substitution therapy in pancreatic insufficiency);
– presence of a shell that protects enzymes from digestion by gastric juice;
– the size of the tablet or pellets that fill the capsules (evacuation of the drug from the stomach simultaneously with food occurs if the size of its particles does not exceed 2 mm)
– presence of bile acids in the drug (bile acids improve lipid digestion, increase absorption of fatty acids and cholesterol, cause increased pancreatic secretion). However, high levels of bile acids in the intestine with intensive enzyme therapy can cause chologenic diarrhea.
Digestive enzymes are indicated for patients with gastric secretion disorders (hypo- and anacidic chronic gastritis, conditions after gastric resection). After gastric surgery can develop malabsorption syndrome associated with many different factors: decreased production of hydrochloric acid and pepsin; disturbance of chyme mixing and its mechanical processing; disturbance of fractional chyme flow into small intestine; accelerated passage through small intestine; decreased endogenous pancreatic secretion stimulation; asynchronous flow of pancreatic juice, bile and chyme into small intestine . Treatment of postgastroresection disorders requires complex therapy with antacids, agents affecting motility of the gastrointestinal tract, digestive enzymes.
In hypoacidic states accompanied by decreased availability of nutrients, preparations containing bile are indicated. These drugs help to increase production of bile and pancreatic juice, they should be taken 1-3 tablets during or immediately after a meal (without chewing) 3-4 times a day for up to 2 months.
Drugs containing bile should be used with caution in patients with chronic hepatitis or cirrhosis of the liver, because bile acids enter the liver via enterohepatic route, where they are metabolized, as well as in cholestatic diseases, ulcer disease, Crohn’s disease and non-specific ulcerative colitis.
Hypoacid gastritis is an indication for prescription of drugs containing components of the gastric mucosa: pepsin and hydrochloric acid. These components provide mechanical and chemical processing of food, first of all – proteins. Proteolysis occurs to the level of polypeptides, which are then broken down by pancreatic proteases and partially to amino acids. Pepsin stimulates pancreatic secretion, so it is contraindicated in patients with chronic pancreatitis, especially in the presence of intraductal hypertension. Preparations containing pepsin are taken at the rate of 0.2-0.5 g pepsin per meal 2-3 times a day before or during meals. For the treatment of patients with reduced acid-forming function of the stomach, preparations containing pure pancreatin, 1 t (4 p/day at the beginning of the meal), have been successfully used recently.
For treatment of hypomotor biliary dyskinesia (hypokinesia) and fat solubilization disorders, enzyme preparations containing bile acids are successfully used. Bile acids and salts increase the contractile function of the gall bladder, normalize the biochemical properties of bile.
Treatment of pancreatitis with severe pain syndrome requires strict dietary restriction, prescription of antisecretory drugs, antispasmodics and preparations of pure pancreatin in high dose. These agents are the most universal for normalization of digestion in the gastrointestinal tract and can be used as part of complex therapy for all types of disorders. Enzyme agents containing pure pancreatin have proteases, amylase, and lipase in their composition. The drug Digestal includes hemocellulase, which provides the breakdown of cellulose. Modern studies show that digestive pancreatic enzymes in the traditional nonenteric form provide pain relief during exacerbations . Pancreatic enzymes ingestion (first of all trypsin) into duodenum destroys secretin and cholecystokinin releasing peptides and causes reduction of pancreatic secretion, providing functional peace of the organ.
Much hope has been associated with digestive enzymes of plant and fungal origin, primarily because of the high acid resistance of plant and fungal lipases. However, under experimental conditions bacterial lipase proved to be 75 times less active than porcine lipase, and therefore these drugs are not yet used in clinical practice. Pancreatin does not affect gastrointestinal motility, bile secretion, and biliary tract function.
Substitution therapy of exocrine pancreatic insufficiency is necessary in various diseases when atrophy of more than 90% of the organ parenchyma occurs, occurring most often in the late stage of chronic pancreatitis. The indications are steatorrhea (loss of fat in the feces more than 15 g/day, while the norm is up to 7 g/day), progressive weight loss, diarrhea, dyspeptic symptoms. Treatment of extrasecretory pancreatic insufficiency is still a challenge. Currently, the most established therapy can be considered several directions: refusal of alcohol consumption, compliance with a diet with frequent intake of small amounts of food, enzyme replacement therapy, control of vitamin deficiency, analgesics (paracetamol, tramadol), psychotropic drugs.
Enzyme therapy in the development of exocrine pancreatic insufficiency requires the use of capsules containing microgranules (microtablets) of pancreatin. In disorders of nutrient hydrolysis the capsules are reliably more effective than pancreatin tablets of usual size. The peculiarity of these preparations is that the enzymes they contain are released only in alkaline environment of the small intestine and thus avoid destruction by gastric juice (Fig. 3), which makes replacement therapy for pancreatic steatorrhea much more effective. Drug stability in acid medium is a very important property of the preparations (the main components of enzyme preparations – lipase and trypsin rapidly lose their activity in acid medium: lipase at pH=4, trypsin at pH=3; before a drug enters duodenum up to 92% of lipase can be destroyed). This property considerably increases efficiency of substitution therapy and reduces or eliminates necessity of prescription of drugs blocking gastric secretion. Thus, when using the enterosolubilized drug, fat absorption is higher by an average of 20% than when using a conventional agent in the same dose. However, patients with chronic pancreatitis have significantly reduced bicarbonate production, which leads to impaired alkalization in the duodenum and impaired activation of the enzymes taken. In this case the effectiveness of the encapsulated enzymes may be significantly reduced.
The downside of drugs in enterosolubilic sheath is that enzymes do not have time to activate in duodenum, the main site of pancreatic regulatory peptide production. Low protease activity in duodenum does not allow to interrupt stimulation of pancreatic secretion by negative feedback mechanism, does not reduce pressure in pancreatic ducts and parenchyma. High intrapancreatic pressure is considered to be the main mechanism of intensive pain development in chronic pancreatitis, that is why encapsulated enzymes are recommended only as substitution therapy, and for pain relief (especially in intraductal hypertension) – traditional pancreatin tablets or powder.
Nevertheless, according to our own data, treatment of chronic pancreatitis with encapsulated pancreatin resulted in significant decrease of the intensity of abdominal pain in the examined patients (p=0,0063; Fig. 4). At the same time the degree of pain reduction reliably depended on the degree of decrease of fecal elastase activity as compared to the initial level (p=0,0219). Thus, the analgesic effect of the therapy directly depended on the degree of suppression of exocrine function of the pancreas in the patient. Exocrine function of the pancreas according to the elastase test (determination of fecal elastase by immunoreactive method) significantly decreased in comparison with the background: 279.46±27.41 μg/g and 254.87±26.74 μg/g (n=52, p=0.0152).
The particle size of microgranulated preparations should not exceed 2 mm, which ensures simultaneous evacuation of food and enzymes from the stomach. Further reduction of pellet size does not lead to an increase in the efficiency of food digestion . Administration of pancreatin capsules at a dose of 16-18 thousand units per meal to patients with chronic pancreatitis after surgical interventions on the pancreas (pancreatoduodenectomy and drainage of the wirsung duct) for 2.5 years allowed to decrease fecal fat loss from 33.6 g/day to 15.3 g/day . There was a statistically reliable increase in body weight of patients and biochemical parameters of the trophological status (serum iron, total iron-binding capacity of blood serum, total number of lymphocytes).
According to Farkas G., Takacs T. et al. (1999), prescription of microgranulated pancreatin at a dose of 25,000 units for patients after pancreas surgery. 3 times a day for 10 days did not lead to changes in pancreas function in comparison with placebo administration . Nevertheless, the therapy performed effectively eliminated the symptoms of maldigestion, stabilized body weight (in the comparison group – weight loss by 3.5 kg during the same period) and increased carbohydrate breakdown by 35%.
Adequate therapy of exocrine pancreatic insufficiency syndrome requires the use of high doses of enzyme preparations. Usually it is necessary to use enzymes in capsulated form. Dosing regimen is as follows: 1-4 capsules of enzyme preparations at main meals (at the beginning of meals) and 1 capsule (tablet) at small meals. The patient should avoid eating food rich in fiber because it reduces enzyme activity both in vitro and in vivo. Lipase is the main component of the enzyme medication that determines the effectiveness of therapy for digestive disorders. At the same time proteases and above all trypsin are the main lipase inhibitors. Therefore, to stop steatorrhea one should not seek a significant increase in proteolytic activity of the chyme. Often a high dose of enzymes entering the stomach does not provide the desired result: the main components of enzyme preparations – lipase and trypsin quickly lose activity in an acidic environment. Therefore, the effectiveness of enzyme therapy can be increased by simultaneous prescription of antacids or antisecretory drugs, but it should be remembered that antacids containing calcium or magnesium weaken the effect of enzyme drugs.
Many open questions remain in assessing the efficacy of enzyme therapy, particularly replacement therapy, and in determining the optimal doses. For example, there are two groups of patients: those patients in whom the secretion of PZ exceeds 10%, but steatorrhea is nevertheless observed; and those in whom lipase secretion is practically absent, but normal digestion and absorption of fat is preserved. This may be due, respectively, to the different reserve secretory capacity of the pancreas and to the action of nonpancreatic lipases (produced by the mucosa of the tongue and stomach, mainly the upper part of the large curvature). Researchers estimate that patients with exocrine pancreatic insufficiency may absorb more than 50% of their dietary fat in the absence of detectable pancreatic lipase activity. It has been shown that in patients with severe pancreatitis with steatorrhea when eating 100 g of fat with food, 20-50 g of fat can be absorbed without enzyme replacement therapy. According to Abrams C.K., Hamosh M. et al. (1987) , in patients with pancreatic exocrine insufficiency nonpancreatic lipases give more than 90% of total lipolytic activity at the level of duodeno-eunal transition, while in healthy people – 7%. This observation may explain, at least in part, why some patients do not require enzyme replacement therapy after total pancreatectomy surgery.
However, in a double-blind, crossover study by Neoptolemos J.P., Ghaneh P. et al. (1999) in 37 XP patients with external secretory insufficiency after extensive pancreatic resection no significant differences in stool frequency, fecal volume and daily fecal fat loss on standard or high dose pancreatin were observed. In this connection the authors conclude that the main advantage of modern preparations with high pancreatin content in one capsule is convenience for the patient, which ensures more precise compliance with the therapy regimen. In another study when prescribing encapsulated medication to patients with chronic pancreatitis no dependence of fat content in feces on the drug dose was found , which suggests the presence of a certain threshold of enzyme efficiency, upon reaching which further increase of the dose does not lead to steatorrhea reduction.
Treatment of patients with disorders of motility and tone of the large intestine, for example, in irritable bowel syndrome, in addition to antispasmodics, coagulation, psychotropic drugs sometimes requires use of digestive enzymes. The use of enzymes, which include components of bile, causes an increase in intestinal motility and contributes to the resolution of constipation patients have. Enzyme preparations that contain hemicellulase (Digestal) improve the digestion of plant foods and reduce abdominal bloating, which has a good symptomatic effect.
Healthy individuals can take digestive enzymes to relieve dyspeptic symptoms after overeating. Episodic administration of small doses of digestive enzymes (1-2 tablets) has no effect on pancreatic function and is considered safe. In this situation, preparations with bile components have proven to be the best.
The reasons for ineffectiveness of substitution therapy can be related to both inaccurate diagnosis of the disease and inadequate therapy. Sometimes, in order to reduce the cost of the treatment course, a lower dose of the drug is prescribed. Patients may not adhere to the prescribed regimen correctly: reduce the frequency of administration or take the enzyme at the wrong time (before or after meals). Enzyme preparations are ineffective in steatorrhea of extrapancreatic origin (celiac disease, giardiasis, etc.). The action of enzymes is impaired in intestinal motility disorders. Incorrect treatment regimen: prescription of enzymes that do not have an acid-protective shell without inhibitors of gastric secretion; use of drugs that do not enter the duodenum simultaneously with food due to the large size of the pellets.
Side effects of enzyme therapy are usually not severe. The most dangerous of them – development of fibrosing colopathy – occurs in children with cystic fibrosis when very high doses of encapsulated enzymes are taken for a long time – more than 50,000 units of lipolytic activity per 1 kg of weight per day. In addition, patients may have painful sensations in the mouth (usually when taking enzymes in powder form), skin irritation in the perianal area, a feeling of discomfort in the abdomen. Prolonged enzyme therapy in high doses may cause hyperuricemia, in some cases there are allergic reactions to porcine protein (including relatives of patients with exocrine pancreatic insufficiency and medical personnel). Formation of complexes with enzymes sometimes leads to impaired absorption of folic acid.