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PubMed · 2589294

Postmortem tricyclic antidepressant concentrations. Lethal versus nonlethal levels.

Abstract

Evidence has accumulated that postmortem release of tissue-bound tricyclic antidepressants (TCAs) may cause falsely elevated postmortem blood levels, thus rendering it more difficult to determine if the cause of death was an overdose. This study, a review of 24 TCA-related deaths, is aimed at defining the practical significance of such a problem and providing a workable approach to interpreting postmortem TCA levels. Deaths clearly due to TCA drugs were compared with deaths that were not caused by TCA drugs, but in which the decedent's postmortem blood tested positive for TCA medications. There is little evidence that postmortem elevations in blood TCA levels cause frequent problems in differentiating lethal from nonlethal levels (overdose from nonoverdose cases). The data suggest that using a heart blood level of 0.100 mg/dl as an indicator of lethality is practical at the present time and poses little likelihood of error. Isolated cases suggest that postmortem TCA increases can occur; further work is needed in this area to clarify more fully the significance and frequency of such cases. At present, it seems prudent to utilize peripheral blood samples for TCA testing on autopsy material, if a conservative estimate of TCA concentration is desired, possibly augmented by liver TCA levels and parent-metabolite ratios if money, facilities, and time permit.

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BibTeXRIS

R Hanzlick. 1989. Postmortem tricyclic antidepressant concentrations. Lethal versus nonlethal levels.. https://doi.org/10.1097/00000433-198912000-00009

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Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline.

The inwardly rectifying K(+) (Kir) channel Kir4.1 is responsible for astroglial K(+) buffering. We examined the effects of nortriptyline, a tricyclic antidepressant (TCA), on Kir4.1 channel currents heterologously expressed in HEK293T cells, using a whole-cell patch-clamp technique. Nortriptyline (3-300 microM) reversibly inhibited Kir4.1 currents in a concentration-dependent manner, whereas it marginally affected neuronal Kir2.1 currents. The inhibition of Kir4.1 channels by nortriptyline depended on the voltage difference from the K(+) equilibrium potential (E(K)), with greater potency at more positive potentials. Blocking kinetics of the drug could be described by first-order kinetics, where dissociation of the drug slowed down and association accelerated as the membrane was depolarized. The dissociation constant (K(d)) of nortriptyline for Kir4.1 inhibition was 28.1 microM at E(K). Other TCAs, such as amitriptyline, desipramine, and imipramine, also inhibited Kir4.1 currents in a similar voltage-dependent fashion. This study shows for the first time that nortriptyline and related TCAs cause a concentration-, voltage-, and time-dependent inhibition of astroglial K(+)-buffering Kir4.1 channels, which might be involved in therapeutic and/or adverse actions of the drugs.

Antidepressive Agents, Tricyclic↗