Key result
Simulated increasing doses of amitriptyline prolonged action potential duration, with significant ΔAPD90 at doses ≥1000 mg and early afterdepolarizations at 10,000 mg.
Why the study?
Do increasing doses of amitriptyline alter the electrophysiology of human ventricular cardiomyocytes?
Do increasing doses of amitriptyline alter the electrophysiology of human ventricular cardiomyocytes?
A simulation study demonstrates that while therapeutic doses of amitriptyline do not cause repolarization abnormalities, massive overdoses (≥1000 mg) significantly prolong action potential duration and can induce early afterdepolarizations.
Simulation of AMI effects on ventricular AP may guide modeling; leaves open experimental and clinical validation.
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 I Ca(L) , I Kr , and I Na 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.
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Tylutki et al. (2016) studied Amitriptyline overdose / Arrhythmia. Amitriptyline and nortriptyline was evaluated on APD50, APD90, triangulation, and ΔAPD90. Simulated increasing doses of amitriptyline prolonged action potential duration, with significant ΔAPD90 at doses ≥1000 mg and early afterdepolarizations at 10,000 mg.
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