Cyclopenthiazide

Many frequently prescribed drugs are suspected to cause acute pancreatitis (AP). The goal of this paper is to bring to light the often occult but real problem of drug-induced pancreatitis (DIP).

We searched the National Library of Medicine/Pubmed for reported cases of DIP from 1966 to April 30, 2004. Medications implicated in AP are classified based on the strength of evidence into one of three classes of drugs associated with pancreatitis. We reviewed the top 100 prescription medications in the United States for their association with AP.

Class I medications (medications implicated in greater than 20 reported cases of acute pancreatitis with at least one documented case following reexposure): didanosine, asparaginase, azathioprine, valproic acid, pentavalent antimonials, pentamidine, mercaptopurine, mesalamine, estrogen preparations, opiates, tetracycline, cytarabine, steroids, trimethoprim/sulfamethoxazole, sulfasalazine, furosemide, and sulindac. Class II medications (medications implicated in more than 10 cases of acute pancreatitis): rifampin, lamivudine, octreotide, carbamazepine, acetaminophen, phenformin, interferon alfa-2b, enalapril, hydrochlorothiazide, cisplatin, erythromycin, and cyclopenthiazide. Class III medications (all medications reported to be associated with pancreatitis). Of the top 100 most frequently prescribed medications in the United States, 44 have been implicated in AP, 14 of them fall into either Class I or II of medications associated with AP.

Among adverse drug reactions, pancreatitis is often-ignored because of the difficulty in implicating a drug as its cause. The physician should have a high index of suspicion for DIP, especially in specific subpopulations such as geriatric patients who may be on multiple medications, HIV+ patients, cancer patients, and patients receiving immunomodulating agents.

A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis procedure for acidic drugs and poisons.