Electrophysiological Actions

Dofetilide's mechanism of action involves blockade of the cardiac ion channel that carries the rapid component of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IK1) over a wide range of concentrations. At plasma concentrations within the therapeutic range, dofetilide has no effect on sodium channels or on either ar or p-adreno-ceptors.

Dofetilide blocks IKr in all myocardial tissues. It blocks open channels, and its binding and release from the channels is voltage dependent. The effects of dofetilide are exaggerated when the extracellular potassium concentration is reduced, which is important, as many patients may be receiving diuretics concurrently. Conversely, hyperkalemia decreases the effects of dofetilide, which may limit its efficacy when local hy-perkalemia occurs, such as during myocardial ischemia. Dofetilide demonstrates reverse use dependence, that is, less influence on the action potential at faster heart rates. This is likely due to a greater influence of other repolarizing currents such as the slowly activating component of the delayed rectifier current (IKs).

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