Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Bio-Algorithms and Med-Systems

Editor-in-Chief: Roterman-Konieczna , Irena


CiteScore 2017: 0.43

SCImago Journal Rank (SJR) 2017: 0.160
Source Normalized Impact per Paper (SNIP) 2017: 0.223

Online
ISSN
1896-530X
See all formats and pricing
More options …

The effect of increasing amitriptyline doses on cardiomyocytes’ electrophysiology – simulation study

Zofia Tylutki
  • Corresponding author
  • Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Jagiellonian University Medical College, Krakow, Poland
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jakob Jornil / Sebastian Polak
  • Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Jagiellonian University Medical College, Krakow, Poland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-02-12 | DOI: https://doi.org/10.1515/bams-2015-0043

Abstract

Background: Overdoses of tricyclic antidepressants may lead to arrhythmia. The aim of the study was to simulate the effect of increasing concentrations of amitriptyline (AMI) and its metabolite, nortriptyline, on the action potential of human ventricular cell.

Methods: Simulations were performed in Cardiac Safety Simulator platform with the use of the O’Hara-Rudy model. Input data included literature-derived, drug-specific IC50 values for ICa(L), IKr, and INa currents. Individual concentrations of AMI and nortriptyline were simulated in Simcyp. Nine single doses (mg) were tested: 5, 10, 50, 100, 300, 500, 1000, 5000, and 10,000.

Results: The values of simulated endpoints (APD50, APD90, triangulation, and ΔAPD90) increase with drug concentrations. ΔAPD90 was statistically significant for doses up from 1000 mg. EADs were observed after administration of 10,000-mg AMI.

Conclusions: The consequences of various doses of AMI on the single cardiac myocytes were simulated in our study. Repolarization abnormalities were not expected for the therapeutic doses. EADs may be observed for very high doses of AMI.

Keywords: drug safety; modeling; simulation

References

  • 1.

    Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Medicine 2011;9:90.Web of ScienceCrossrefGoogle Scholar

  • 2.

    Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013;14:334–85.Web of ScienceGoogle Scholar

  • 3.

    Thanacoody HK, Simon HL. Tricyclic antidepressant poisoning. Toxicol Rev 2005;24:205–14.CrossrefGoogle Scholar

  • 4.

    Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen PJ, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015;29:459–525.CrossrefGoogle Scholar

  • 5.

    Ansel GM, Coyne K, Arnold S, Nelson SD. Mechanisms of ventricular arrhythmia during amitriptyline toxicity. J Cardiovasc Pharmacol 1993;22:798–803.CrossrefGoogle Scholar

  • 6.

    Glassman AH, Bigger Jr JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatr 2001;158:1774–82.CrossrefGoogle Scholar

  • 7.

    Glinka A, Polak S. The effects of six antipsychotic agents on QTc – An attempt to mimic clinical trial through simulation including variability in the population. Comput Biol Med 2014;47:20–6.CrossrefWeb of ScienceGoogle Scholar

  • 8.

    O’Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Computat Biol 2011;7:e1002061.Web of ScienceCrossrefGoogle Scholar

  • 9.

    Guo L, Guthrie H. Automated electrophysiology in the preclinical evaluation of drugs for potential QT prolongation. J Pharmacol Toxicol Methods 2005;52:123–35.CrossrefGoogle Scholar

  • 10.

    Harmer AR, Abi-Gerges N, Woods EA, Lawrance CL, Small BG, Small BG, et al. Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks™. J Pharmacol Toxicol Methods 2008;57:30–41.Google Scholar

  • 11.

    Park KS, Kong ID, Park KC, Lee JW. Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat ventricular myocytes. Yonsei Med J 1999;40:144–51.Google Scholar

  • 12.

    Huang XP, Mangano T, Hufeisen S, Setola V, Roth BL. Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting. ASSAY Drug Dev Technol 2010;8:727–42.CrossrefWeb of ScienceGoogle Scholar

  • 13.

    Polak S, Wiśniowska B, Ahamadi M, Mendyk A. Prediction of the hERG potassium channel inhibition potential with use of artificial neural networks. Appl Soft Comput 2011;11:2611–7.Web of ScienceCrossrefGoogle Scholar

  • 14.

    Jamei M, Marciniak S, Edwards D, Wragg K, Feng K, Barnett A, et al. The Simcyp population based simulator: architecture, implementation, and quality assurance. In Silico Pharmacol 2013;1:9.Google Scholar

  • 15.

    Jornil J, Jensen KG, Larsen F, Linnet K. Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator. Eur J Pharm Sci 2011;44:265–72.CrossrefWeb of ScienceGoogle Scholar

  • 16.

    Fijorek K, Patel N, Klima Ł, Stolarz-Skrzypek K, Kawecka-Jaszcz K, Polak S. Age and gender dependent heart rate circadian model development and performance verification on the proarrhythmic drug case study. Theor Biol Med Modell 2013;10:7.CrossrefWeb of ScienceGoogle Scholar

  • 17.

    Weiss JN, Garfinkel A, Karagueuzian HS, Chen PS, Qu Z. Early afterdepolarizations and cardiac arrhythmias. Heart Rythm 2010;7:1891–9.CrossrefGoogle Scholar

  • 18.

    Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. Br Med J 2013;346:f288.Web of ScienceGoogle Scholar

  • 19.

    Jeon SH, Jaekal J, Lee SH, Choi BH, Kim KS, Jeong HS, et al. Effects of nortriptyline on QT prolongation: a safety pharmacology study. Hum Exp Toxicol 2011;30:1649–56.Web of ScienceCrossrefGoogle Scholar

  • 20.

    Davison ET. Amitriptyline-induced torsade de pointes. Successful therapy with atrial pacing. J Electrocardiol 1985;18:299–301.CrossrefGoogle Scholar

  • 21.

    Güloğlu C, Orak M, Üstündağ M, Altunci YA. Analysis of amitriptyline overdose in emergency medicine. Emerg Med J 2011;28:296–9.CrossrefWeb of ScienceGoogle Scholar

  • 22.

    Volders PGA, Vos MA, Szabo B, Sipido KR, de Groot SH, Gorgels AP, et al. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res 2000;46:376–92.CrossrefGoogle Scholar

About the article

Corresponding author: Zofia Tylutki, Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str. Cracow 30-688, Poland, E-mail:


Received: 2015-11-27

Accepted: 2015-12-14

Published Online: 2016-02-12

Published in Print: 2016-03-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: Project was financed by the National Science Centre, Poland, project number 2014/13/N/NZ7/00254.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Bio-Algorithms and Med-Systems, Volume 12, Issue 1, Pages 33–38, ISSN (Online) 1896-530X, ISSN (Print) 1895-9091, DOI: https://doi.org/10.1515/bams-2015-0043.

Export Citation

©2016 by De Gruyter.Get Permission

Comments (0)

Please log in or register to comment.
Log in