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6.33.5.2.1.3 Class 3: Potassium channel blockers

There are many cardiac potassium channels including the transient outward (Ito), the ultrarapid, rapid, and slow components of delayed rectifier (IKur, IK„ and IK„ respectively) and inward rectifier (IK4). Except for IKr and IKs blockers, most potassium channel blockers, such as the Ito blocker tedisamil (Figure 8), are only partially specific for individual subtypes of potassium channels. Currently, only selective IKr blockers and a mixed channel blocker like amiodarone are used clinically.

6.33.5.2.1.3.1 Selective IKr blockers: dofetilide, ibutilide, D-sotalol The prototypical drug is D-sotalol, the adrenoceptor-inactive enantiomer of the ^-adrenoceptor blocker, DL-sotalol (Figure 9). D-Sotalol, a methanesulfo-nanilide, prolongs ventricular cardiac action potentials by blocking IKr. Methanesulfonanilide derivatives include ibutilide, dofetilide, E4031, and almokalant (Figure 9).

• Mechanism: Methanesulfonanilide derivatives block the open channel configuration. They appear to bind within the transmembrane pore at a fairly well-defined site. All the derivatives are very potent (acting at subnanomolar concentrations) and are specific for the IKr current, especially dofetilide derivatives.

• Effectiveness: The IKr blocker sotalol is used to treat atrial flutter and fibrillation only if the patient is highly symptomatic, since its use is associated with dangerous arrhythmias. Sotalol is also used to terminate life-threatening sustained VT. Dofetilide is used to maintain sinus rhythm in patients with atrial flutter and fibrillation who have been converted to sinus rhythm. On the other hand, rapid intravenous infusion of ibutilide is used for the conversion of atrial arrhythmias to sinus rhythm. However, the usefulness of these IKr blockers is limited by a reverse frequency-dependent profile that results in excessive drug effects at slow heart rates. This not only increases their propensity to cause drug-induced proarrhythmias, but results in a loss of effectiveness at fast heart rates, the opposite of what is needed for tachyarrhythmias.

14 Tedisamil

Figure 8 Structure of tedisamil (Ito blocker).

Figure 8 Structure of tedisamil (Ito blocker).

15 Sotalol

16 Ibutilide

15 Sotalol

16 Ibutilide

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