Pharmacokinetic/pharmacodynamic modeling of cardiac toxicity in human acute overdoses: utility and limitations

Abstract

Background: Hypotension, cardiac failure, QT interval prolongation, dysrhythmias, and conduction disturbances are common complications of overdoses with cardiotoxicants. Pharmacokinetic/pharmacodynamic (PK/PD) relationships are useful to assess diagnosis, prognosis, and treatment efficacy in acute poisonings. Objective: To review the utility and limits of PK/PD studies of cardiac toxicity. Methods: Discussion of various models, mainly those obtained in digitalis, cyanide, venlafaxine and citalopram poisonings. Results/conclusions: A sigmoidal E_max model appears adequate to represent the PK/PD relationships in cardiotoxic poisonings. PK/PD correlations investigate the discrepancies between the time course of the effect magnitude and its evolving concentrations. They may help in understanding the mechanisms of occurrence as well as disappearance of a cardiotoxic effect. When data are sparse, population-based PK/PD modeling using computer-intensive algorithms is helpful to estimate population mean values of PK parameters as well as their individual variability. Further PK/PD studies are needed in medical toxicology to allow understanding of the meaning of blood toxicant concentration in acute poisonings and thus improve management.

Keywords::

• antidote
• cardiac failure
• cardiac toxicity
• citalopram
• conduction disturbance
• cyanide
• digitalis
• dysrhytmia
• hypotension
• pharmacokinetic/pharmacodynamic relationship
• poisoning
• venlafaxine

Acknowledgments

The authors would like to acknowledge Stephen W Borron, from the Division of Emergency Medicine (Surgery), University of Texas Health Science Center at San Antonio, USA for his helpful review of this manuscript.

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