Fatal consequence of short-term benzodiazepine administration followed by proton-pump-inhibitor therapy
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ORRESPONDENCE Correspondence
Fatal Consequence of Short-Term Benzodiazepine Administration Followed by Proton-Pump-Inhibitor Therapy O. Peschel, G. Roider, G. Drasch, and W. Eisenmenger Institute for Forensic Medicine, University of Munich, München, Germany Sir, It is well established that omeprazole influences the catabolism of several benzodiazepines resulting in potentially acute intoxication (1–3). No fatal long-term sequelae of successive application of omeprazole after therapy with benzodiazepines has yet been reported, however. A 60-year-old man suffering from an acute postoperative confusional state was treated with dipotassium clorazepate (metabolized to nordazepam) 200 mg per day from days 1 to 6. After discharge from the hospital on day 7, this medication was discontinued because of presumed side effects. On the same day, diclofenac and omeprazole were commenced. The patient had to be re-admitted to a different hospital on postoperative day 16 as he displayed increasing drowsiness and disorientation. Nordazepam intoxication was diagnosed on day 18 with significantly increased serum levels up to 1.97 mg/L (therapeutic range 0.02–0.8 mg/L).
The further clinical course was complicated by pneumonia, liver and renal failure, and progressive cardiac failure until death occurred owing to multi-organ failure on day 60 (nordazepam serum level in autopsy material 0.019 mg/L). Omeprazole therapy had taken place between days 7 and 44. There was no prescription of any benzodiazepine after day 6. Continued administration of benzodiazepine had initially been suspected when the markedly elevated benzodiazepine levels persisted despite the fact that nordazepam officially had been discontinued. This led to a criminal investigation. It is well established that the half-life of nordazepam (usually 25–82 hours) may be extended in older patients (up to 200 hours) as a result of impaired renal and/or liver function [1]). The daily dose given initially in this case was in the upper range, however, it was given only for a short period
Fig. 1. Kinetics of nordazepam metabolism after administration of clorazepate (200 mg per day for 6 days) in average conditions (normal, half-life 48 hours), in geriatric patients (estimated half-life 180 hours), and in geriatric patients with additional omeprazole inhibition (estimated half-life 360 hours).
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210 _____________________________________________________________________________________Peschel et al. of time. Normally, elevated benzodiazepine levels resolve within a few days after discontinuation without a negative effect on patient outcome. Clorazepate and omeprazole are frequently prescribed drugs. Nordazepam, as the major metabolite and active principle of clorazepate and omeprazole, are both metabolized via cytochrome P450 isoenzyme CYP2C19 (3). Therefore, the half-life of nordazepam is significantly extended owing to the pharmacokinetic interaction. According to a recent publication, a prolonged nordazepam half-life up to 550 hours has been estimated when clorazepate and omep
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