Prolonged sedation due to accumulation of conjugated metabolites of midazolam

doi:10.1016/S0140-6736(95)91209-6

The Lancet

Volume 346, Issue 8968, 15 July 1995, Pages 145-147

https://doi.org/10.1016/S0140-6736(95)91209-6 Get rights and content

Abstract

Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, α-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. We report five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated α-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated α-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1·4 nmol/L) or unconjugated α-hydroxymidazolam (2·2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.

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ArticlesProlonged sedation due to accumulation of conjugated metabolites of midazolam

Abstract

Anal Biochem

Lancet

Lancet

Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?

Clin Pharmacol Ther

The effects of acute changes in renal function on the pharmacokinetics of midazolam during long-term infusion in ICU patients

Acta Anaesth Belg

Pharmacokinetics and bioavailability of midazolam in man

Br J Clin Pharmacol

Controlled sedation with alphaxalone-alphadolsone

BMJ

Articles
Prolonged sedation due to accumulation of conjugated metabolites of midazolam