Despite these limitations, as illustrated in Figure 1, following a thorough algorithm can aid in detecting cases of drug-induced pancreatitis that would otherwise have been difficult to diagnose . In accordance with the aforementioned limitations, evidence implicating numerous medications is inconsistent and, at times, even contradictory. Hence, although not uniform, nor universally accepted, official tier systems exist to help quantify the likelihood of a drug to be established as a culprit of acute pancreatitis. The earliest classification system was developed in 1980 and was designed to include three classes; Class I: Included drugs that were implicated to induce pancreatitis in a minimum of 20 cases of which at least one case documented drug re-exposure, Class II: Included drugs that were implicated to induce pancreatitis in 10-20 cases with or without documented drug re-exposure, and Class III: Included all drugs implicated in pancreatitis. Trivedi et al reviewed the top 100 prescription medications in the United States for their association with acute pancreatitis using this three-tier classification system. They noted that, of the top 100 most frequently prescribed medications, 44 were Class III pancreatitis medications. Additionally, 14 of these medications were Class I or II. The most recent classification system was developed by Badalov et al, in which the authors categorized implicated drugs into four classes . Class I drugs are medications in which a re-challenge was established in at least one case report. This class is further divided into whether other causes of acute pancreatitis were ruled out or not . Class II drugs are medications in which there is a latency period in 75% of at least four reported cases,seedling grow rack all with no evidence of re-challenge. Class III drugs are medications that neither a re-challenge nor a consistent latency period was established but had two or more case reports published. Class IV drugs are medications that neither a re-challenge nor a consistent latency period was established, and only 1 case report had been published.

Additionally, the Naranjo adverse drug reaction probability scale can be helpful in establishing the degree of association between a drug and an adverse reaction. This tool determines the likelihood of an adverse drug reaction based on the cumulative score on 10 questions. A score of < 1 signifies a doubtful drug reaction, 1-4 a possible drug reaction, 5-8 a probable drug reaction, and > 9 a definitive drug reaction . Finally, and most recently, our proposed specific drug-induced pancreatitis probability scale can serve as a standardized tool for determining the likelihood of drug-induced pancreatitis based on the aggregate score from a series of 10 questions. A score of < 2 suggests doubtful DIP, 3-5 possible DIP, 6-8 probable DIP, and > 9 highly probable DIP . We believe this tool, in particular, enhances one’s ability to accurately identify and implicate potential acute pancreatitis-causing drugs. While consensus has yet to be reached regarding the cause of drug-induced pancreatitis in many cases, numerous potential mechanisms have been speculated. These include, pancreatic/biliary duct constriction, cytotoxic effects, metabolic effects, accumulation of a toxic metabolite or intermediary, and idiosyncratic and/or hypersensitivity reaction, with idiosyncratic response or direct toxic effect likely accounting for the majority of cases. Studies concerning the incidence of drug-induced pancreatitis have established a range of 0.3% to 1.4% of all acute pancreatitis cases being due to drugs. Certain medications such as azathioprine/mercaptopurine and didanosine are well-known culprits of drug-induced pancreatitis with incidences of 5% and 23% respectively. As illustrated in Table 3, compiling a list of drug classes implicated in pancreatitis may yield clinical use owning to increased clinician awareness of other medications in these classes. Among the many drugs that have been associated with pancreatitis, statins have been increasingly reported as a cause of acute pancreatitis. In fact, as numerous members of this class have been implicated in acute pancreatitis, statin-induced pancreatitis may indeed be a class-effect.

Mechanisms of action of statin-induced acute pancreatitis are associated with rhabdomyolytic and cytochrome P-450 interactions leading to an immune-mediated inflammatory response, direct cellular toxicity, or perhaps a metabolic effect. As with many other drugs, its true prevalence in acute pancreatitis remains unknown, as the onset of statin-induced pancreatitis has been observed from hours to years after treatment. Interestingly, the degree of P-450 CYPA4 inhibition correlates with individual statin safety profiles. Although rare, several 5-aminosalicylic acid -induced acute pancreatitis cases have been published in the literature. Interestingly, both oral and enema mesalamine preparations have been implicated in causing pancreatitis within days. In addition, sulfasalazine has been implicated in inducing pancreatitis perhaps through an immune-mediated mechanism . In general, however, a hypersensitivity mechanism seems to be involved and pancreatitis can occur from days to years after starting mesalamine therapy.Metronidazole has been reported in association with acute pancreatitis, although the mechanism is not fully known. Free-radical production, immune-mediated, direct toxic affect, and metabolic effects have been suggested as possible pathophysiological mechanisms. Notably, a study showed that patients receiving metronidazole as part of Helicobacter pylori triple-therapy have an approximate eight-fold increased risk of acute pancreatitis. The tetracycline class has also been associated with acute pancreatitis, with the mechanism believed to be a direct toxic-effect, or hypersensitivity reaction. In addition, numerous cases of erythromycin-induced pancreatitis have been reported to date.

Although less established, other antibiotics such as ampicillin, ceftriaxone, clarithromycin, trimethoprim-sulfamethoxazole, and nitrofurantoin have been implicated in pancreatitis as well. Numerous steroids have been associated with inducing acute pancreatitis nearly all with a short latency period. As a large proportion of these cases resulted in death, it has been suggested that this drug class may be linked to a more severe disease course. The most common non-steroidal anti-inflammatory drugs that have been reported to cause pancreatitis are sulindac and salicylates, with latency ranging from weeks to years, however others have been implicated as well. A clear limitation that exists is the fact that NSAIDs may be initiated in response to early symptoms of unrecognized pancreatitis leading to erroneously attributing the pancreatitis to this class of medication. Interestingly, naproxen has been recommended as the preferred analgesic in this scenario owning to its limited risk of inducing acute pancreatitis. The mechanism being, a structural effect on the sphincter of Oddi leading to acute pancreatitis. Of note, both diclofenac and indomethacin may significantly reduce the risk of acute pancreatitis post-endoscopic retrograde cholangiopancreatography. Immunotherapy agents have long been associated with acute pancreatitis, however their increased use in recent decades has led to a concomitant increase in immunotherapy-associated pancreatitis. Interleukin-2 immunotherapy-associated pancreatitis in particular has been reported. The mechanism of injury is believed to be either immune-mediated or a direct drug toxicity. Newer programmed cell death protein 1 blockers and anti-cytotoxic T-lymphocyte-associated protein 4 agents have been associated with acute-pancreatitis as well. The exact mechanism is currently unknown,greenhouse growing racks but it is speculated to be associated with Tlymphocyte mediated inflammation. There have been many well-documented case reports of acute pancreatitis due to Angiotensin-converting-enzyme inhibitors. One case-control study suggested a dose-dependent correlation with an odds ratio of 1.5. While enalapril has been the most extensively reported culprit in this class, other agents have been described in the literature as well. Similar to ACE-Is, angiotensin receptor blockers has also been implicated in acutepancreatitis. Interestingly, the latency period between ACE-I initiation and an associated pancreatitis event may range from days to years and may be associated with severe disease. The proposed mechanism involved is due to decreased bradykinin degradation, increasing pancreatic vascularity and edema, and pancreatic enzyme trapping causing local tissue damage secondary to pancreatic duct obstruction. Although proven to be relatively safe for the management of type 2 diabetes mellitus, numerous classes of oral anti-glycemic agents including biguanides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogues, and sodium glucose co-transporter-2 inhibitors have been associated with acute pancreatitis.

The highest incidence is reported with GLP-1 analogues, of which exenatide has the highest association with an up to 6-fold increase in the rate noted in post-marketing surveillance. The proposed mechanism is pancreatic acinar cell hypertrophy, the subsequent release of pro-inflammatory cytokines, leading to increased vascular permeability, resulting in pancreatic inflammation. Another hypothesis suggests an obstructive type phenomenon, as an increased incidence of gallstones with the use of GLP-1 analogues has been recorded.As such, many case reports suggesting the association between cannabis and pancreatitis have been published in the literature, and may even suggest a dose-dependent phenomenon. While cannabinoid receptors are found in the islet of Langerhans cells, the exact pathophysiology of cannabis-induced pancreatitis is currently not well-understood. Cocaine-induced pancreatitis has also been reported, and is believed to be due to splanchnic vasoconstriction and thrombotic micro-angiopathy leading to ductal obstruction. Similarly, codeine has also been described in the literature with regards to inducing acute pancreatitis with a mechanism believed to relate to dysfunctional sphincter of Oddi contraction as well.The highly active anti-retroviral therapy therapy drugs have long thought to be associated with the development of acute pancreatitis. The most common offenders include nucleoside reverse transcriptase inhibitors , non-NRTIs , and protease inhibitors. In a large retrospective cohort study including nearly 5000 patients who received antiretroviral therapy, 3.2% developed AP. Furthermore, 5.2% of patients who received didanosine, 4.2% of patients who received a PI plus either an NRTI or a NNRTI, and 3.5% of patients who received NRTIs combined with NNRTIs—developed acute pancreatitis. The exact mechanism by which NRTIs and NNRTIs cause pancreatitis is unidentified, but it is thought to be related to direct drug toxicity or ductal obstruction leading to mitochondrial damage resulting in cellular death and organ damage. PIs are directly related to induction of hypertriglyceridemia which is a well-established cause of pancreatitis in the literature. Diuretics [e.g. furosemide, chlorothiazide, hydrochlorothiazide , and others] have long been implicated in the development of acute pancreatitis, with the majority of cases suggesting a short latency period and a more mild disease course. Notably, HCTZ has well-established side effects of causing hypercalcemia and hyperlipidemia, both of which are well known to lead to acute pancreatitis. HCTZ can further cause hyperparathyroidism, which can also lead to hypercalcemia induced pancreatitis. It has been postulated that furosemide affects the pancreas by causing a hyper-stimulation of secretions leading to a direct toxic injury and/or ischemia. Numerous cases have been reported in which estrogen-containing products were thought to induce acute pancreatitis. Hypercoagulability and hypertriglyceridemia have been speculated as the main cause of inducing pancreatitis in patients taking hormone replacement therapy and oral contraceptives. Nonetheless, patients with existing hypertriglyceridemia and familial hyperlipoproteinemia can have an exacerbation of their underlying condition leading to pancreatitis.Although both H2-blockers and proton-pump inhibitors have been reported in the literature to cause acute pancreatitis, the evidence regarding this relationship is controversial. A retrospective study conducted by Eland et al failed to identify any association of pancreatitis with the use of ranitidine , cimetidine , and/or omeprazole . Case reports in the literature have generally linked pancreatitis in these cases to excessive consumption of antacids which likely was directly related to hypercalcemia. Many cases have linked antidepressants to acute pancreatitis; nonetheless, a population-based study by Nørgaard et al failed to demonstrate a significant association between selective serotonin reuptake inhibitors and acute pancreatitis. Only a mild increase in the risk of pancreatitis was seen with first-time users of SSRI ; however, the results are limited due to confounding variables. A recent meta-analysis demonstrated a significant association between SSRIs and acute pancreatitis. The risk was much higher in the first 2 weeks of following initiation of SSRIs. The exact mechanism by which SSRIs can lead to pancreatitis is unknown, though it is speculated that SSRIs can cause cellular apoptosis, insulin secretioninhibition, and further development of diabetes and chronic pancreatitis as well. Roberge et al additionally reported a case of a patient who developed acute pancreatitis due to an acute overdose of clomipramine. Numerous anti-seizure medications have been associated with inducing pancreatitis, especially in the pediatric population. Interestingly, this class seems to be associated with a more severe disease course that may result in pancreatic necrosis and death. The mechanism has been postulated to involve a direct toxic effect on pancreatic cells causing depletion of superoxide dismutase, catalase, and glutathione peroxidase on a biochemical level. To our knowledge, two cases of vitamin-induced acute pancreatitis have been reported, both involving vitamin D. One involved oral vitamin D, wherein the injury was seemingly related to the hypercalcemic effect of vitamin D.