Antiarrhythmic and Proarrhythmic Potential of Pharmacological Agents

Naveed Muhammad
Antiarrhythmic and Proarrhythmic Potential of Pharmacological Agents.
Doctoral thesis (PhD), University of Szeged.
(2023)

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Abstract in foreign language

Antiarrhythmic therapy in general has a problem ‘especially in the treatment of ventricular arrhythmias’ that the compounds have proarrhythmic potential which is due to the same cellular mechanism that is responsible for their antiarrhythmic properties. Drug-induced arrhythmia can be attributed to either excessive conduction slowing (e.g. with class Ia or Ic Na+ channel blockers) or excessive prolongation of ventricular action potential duration (APD) (e.g. with class III antiarrhythmic agents), or both. The aim of the presents study was to investigate the antiarrhythmic and proarrhythmic potential of some pharmacological agents. We therefore thoroughly investigated and compared the kinetics of these Na+ channel blockers to provide further experimental data and to differentiate between their antiarrhythmic and proarrhythmic properties. In the present study, conventional microelectrode and patch clamp techniques were used to measure the action potential (AP) parameters and the transmembrane ionic currents underlying the AP, respectively. The results show that GS967 inhibits INaP similarly to the class Ib antiarrhythmic drug mexiletine, but with higher potency and three fold faster offset kinetics. Both GS967 and mexiletine significantly depressed V+max at high stimulation rates. Flecainide lengthened APD only at faster stimulation frequencies having cycle length (CL) shorter than 500 ms and increased the APDs of early extrasystoles noticeably. Moreover, flecainide reduced V+max in the entire frequency range exhibiting much slower offset kinetics than mexiletine. Similarly, quinidine depressed V+max use-dependently showing slower offset kinetics than mexiletine. Although, quinidine slowed the restitution kinetics of APD, however, it exhibited a reverse rate-dependent prolongation on APD90. In addition, acute desethylamiodarone (DEA) administration exerted a mild but not reverse rate-dependent APD90 prolongation and significant V+max inhibition at short CLs. Furthermore, cannabidiol lengthened APD90 significantly at the concentration of 5 µM without changing any other AP parameter significantly. These findings suggest that the frequency dependence, restitution kinetics and onset kinetics are important electrophysiological determinants which can discriminate Na+ channel blockers with proarrhythmic and antiarrhythmic potential. Moreover, the current data suggest that compounds which do not block impulse conduction at normal heart rate and have a fast recovery such as mexiletine and GS967, can be promising for future drug development. Also the interesting big APD lengthening effect on the early extrasystole observed with flecainide would be probably useful but the effect on sodium current at normal heart rate can be potentially proarrhythmic. Furthermore, the absence of an increase in dispersion of ventricular repolarization with DEA correlates with its clinically observed lower incidence of proarrhythmia. In addition, the physicians should be aware in recognizing of the deleterious effects of compounds that affect the repolarization reserve in co-morbid or polypharmacy patient.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Naveed Muhammad
Hungarian title: Gyógyszerhatású vegyületek antiaritmiás és proritmiás hatékonysága
Supervisor(s):
Supervisor
Position, academic title, institution
MTMT author ID
Varró András
MTA Doktora, Farmakológiai és Farmakoterápiai Intézet SZTE / SZAOK
10001232
Subjects: 03. Medical and health sciences
03. Medical and health sciences > 03.01. Basic medicine
03. Medical and health sciences > 03.01. Basic medicine > 03.01.06. Pharmacology and pharmacy
Divisions: Doctoral School of Multidisciplinary Medical Sciences
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2023. June 05.
Uncontrolled Keywords: Cardiac Electrophysiology, Antiarrhythmic Drugs, Proarrhythmia, Sodium Channel Inhibitors, Desethylamiodarone, Cannabidiol.
Item ID: 11729
MTMT identifier of the thesis: 34126416
doi: https://doi.org/10.14232/phd.11729
Date Deposited: 2023. Apr. 25. 15:45
Last Modified: 2024. Jan. 25. 09:21
Depository no.: B 7334
URI: https://doktori.bibl.u-szeged.hu/id/eprint/11729
Defence/Citable status: Defended.

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