CHAPTER 13
Pancreatic enzymes
Introduction
Pancreatic enzyme replacement therapy is currently the standard treatment for nutrient malabsorption secondary to pancreatic insufficiency. This treatment is safe and effective in reducing steatorrhea and fat malabsorption. It is well tolerated and has few side effects. Effective therapy has been limited by the ability to replicate the physiologic process of enzyme delivery to the appropriate site ( typically the duodenum) at the appropriate time. The challenges include enzyme destruction in the stomach, lack of adequate mixing with the chyme in the duodenum, and failure to deliver and activate at the appropriate time. The goals of management are to improve absorption of fat, prevent steatorrhea, and improve nutritional status. The use of oral therapy pre-dates the creation of the US Food and Drug Administration (FDA) in 1938, and currently enzyme replacement is the standard therapy in patients diagnosed with malabsorption secondary to pancreatic insufficiency.
The composition and various formulations of pancreatin and pancrelipase affect their use and ability to deliver appropriate amounts of active enzyme to the duodenum. Pancreatin, a crude mixture, is derived from swine or ox pancreas, and each milligram contains no less than 2 United States Pharmacopeia (USP) units of lipase and 25 USP units of amylase and protease activity. Pancrelipase is obtained from swine pancreas and is a more concentrated and purified enzyme preparation. Each milligram contains no less than 24 USP units of lipase and 100 USP units of amylase and protease activity. Because of its higher enzyme content, pancrelipase formulations are favored over pancreatin preparations.
In April 2004, the FDA declared that all orally administered pancreatic enzyme products are considered new drugs and will require the submission and approval of an new drug application (NDA ) if manufacturers wished to continue marketing their products.
An understanding of the labeling of the enzyme preparations is important in order to administer the correct dosages. Preparations in the United States are demarcated by the amount of lipase contained in 1 pill and are dosed in USP units. The USP unit for lipase administration is roughly 3 times the value of international units (IU), which are used in academic publications.
Mechanism of action
The exocrine pancreas is responsible for synthesis and secretion of digestive enzymes including lipase, co-lipase, phospholipase, protease, and amylase, into the duodenum in an alkaline, bicarbonate-rich fluid. In exocrine pancreatic insufficiency, the pancreolipase products contain lipase, protease and amylase. These enzymes catalyze the hydrolysis of fats into monoglycerides, free fatty acids and glycerol, proteins into peptides and amino acids and starches into alpha-dextrins which are then digested by gluco-amylase to maltose and maltriose.
Because lipase is the most sensitive enzyme to proteolytic degradation in acidic environment, fat malabsorption occurs sooner than protein deficiency and is usually the more clinically relevant nutritional problem. Inactivation of pancreatic enzymes occur when pH levels drop below 4.0. The need for protection from proteolytic degradation and gastric acid inactivation has led the development of enteric coated formulations that have been shown to increase absorption compared to uncoated preparations. The uncoated formulations are currently used largely in clinical practice to treat the pain of chronic pancreatitis but not the malabsorption.
Enteric-coated preparations were designed to avoid inactivation in the stomach, as the enzyme is protected from the acidic environment by the coating, and dissolves in the duodenum when pH exceeds 5 to 5.5.
During a meal, normal pancreatic secretion delivers more than 360 000 IU (>1 million USP units) of active lipase into the duodenum in healthy adults, of which 10% is needed to prevent fat malabsorption.
Dosing and schedule of administration
All pancreatic enzyme replacement therapy drugs approved in United States are reviewed in Table 13.1
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