Drug-Induced Acute Pancreatitis

Reports of drug-induced acute pancreatitis (AP) have been published since the 1950s, and each year the list of drugs associated with AP increases. There are many etiological risk factors for AP, including a history of alcohol abuse, gallstones, endoscopic retrograde cholangiopancreatography and manometry, trauma or surgical procedures near the pancreas, certain medications, hyperlipidemia, infection, and chronic hypercalcemia (1, 2). Knowledge of the true incidence of drug-induced AP is dependent on clinicians excluding other possible causes and reporting the event. It can be difficult to rule out other causes of AP, especially in patients who have multiple comorbidities, use multiple medications, and have potentially unknown underlying risk factors. A retrospective study conducted in Germany concluded that the incidence of drug-induced AP is 1.4% (3). A national survey performed in Japan in 1999 reported that 1.2% of all cases of AP were drug induced (2). Drug-induced AP is rare but should not be overlooked in a patient who presents with idiopathic AP. The exocrine function of the pancreas includes the production of digestive enzymes for release into the gastrointestinal tract (1, 4). The acinar cells within the pancreas are responsible for producing the proenzymes, which then are packaged into storage vesicles called zymogens. The zymogens travel through the pancreatic duct and are secreted into the duodenum. Within the duodenum, enterokinase converts trypsinogen to trypsin, and then active trypsin facilitates the conversion of the other pancreatic proenzymes to the active form. AP can occur if there is damage to the acinar cells and/or injury to the pancreatic duct that leads to inappropriate accumulation and activation of proenzymes within the pancreas. The activated pancreatic enzymes digest the cell membranes of the pancreas and activate an inflammatory response, which increases the vascular permeability of the pancreas. Hemorrhage, edema, ischemia, and necrosis can result (1, 4). In severe AP, patients progress to systemic inflammatory response syndrome, sepsis, and multiple organ failure (5). About 3% to 13% of AP cases progress to chronic pancreatitis (2). When AP progresses to a severe illness, patients can experience extended hospital stays and increased health care costs. Neoptolemos and colleagues reported that approximately 25% of patients who develop AP will require intensive care treatment (5). In a retrospective study conducted between January 1992 and December 1996, patients with AP who required intensive care treatment had an average intensive care unit stay of 9 days and an average total hospital stay of 39 days (6). The investigators also concluded that the average overall hospital cost was $96,891. Fortunately, AP patients typically regain complete functional ability and can return to employment and other normal activities (5, 6). In previous years, experts created a classification system that addressed the likelihood that certain drugs would be associated with AP, using the categories of definite, probable, and questionable/possible. Over the years, the list of medications associated with AP has increased. Most recently, Badalov and colleagues expanded the classification system to five categories: Ia, Ib, II, III, and IV (7). Classifications are based on the number of case reports, available rechallenge data, consistent latency period, and ability to exclude other causes of AP. Class Ia includes drugs with at least one case report, evidence of a positive rechallenge, and exclusion of other causes of AP. Class Ib is similar to class Ia, but in this class, other causes of AP could not be ruled out. Criteria for class II drugs include at least four case reports with a consistent latency period for at least 75% of the cases. Class III drugs have at least two case reports but do not have rechallenge data or a consistent latency period. Finally, class IV drugs have one case report without rechallenge data. The Table is a noninclusive list of many medications associated with AP (7–11). Table Drugs and drug classes associated with acute pancreatitis∗ The mechanisms of action for drug-induced AP are based on theories extracted from case reports, case-control studies, animal studies, and other experimental data. In general, some potential mechanisms of action for drug-induced AP include pancreatic duct constriction, cytotoxic and metabolic effects, accumulation of a toxic metabolite or intermediary, and hypersensitivity reactions (12). Other mechanisms for drug-induced AP have been associated with adverse effects of drugs, such as hypertriglyceridemia or chronic hypercalcemia, which are risk factors for AP. More specifically, a potential mechanism of action for angiotensin-converting enzyme (ACE) is a localized angioedema effect within the pancreas. For estrogens and hormone replacement therapy (HRT), arteriolar thrombosis is a theorized mechanism of action. Published case reports of drug-induced AP exist for at least 40 drugs of the top 200 most prescribed medications. This article reviews data on five drug classes or drugs commonly associated with AP: 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, ACE inhibitors, estrogens/HRT, diuretics, highly active antiretroviral therapy (HAART), and valproic acid. Most of these drugs are among the top 200 most prescribed medications for 2007.