Antiarrhythmic Drugs Combining Actions of Classes

No selective channel blocker has yet been shown to unequivocally reduce mortality associated with atrial or ventricular arrhythmias. Amiodarone (38) (Figure 15), a mixed channel blocker that has class 1-4 actions, is the only ion channel blocking antiarrhythmic drug shown clinically to prevent cardiac sudden death. Thus, compounds with appropriate mixed channel blocking effects may be a useful route to new antiarrhythmic drugs. There is experimental evidence that when two different channel blockers are given together, the resulting antiarrhythmic effect is greater than either given alone. As a result, several compounds with combined ion channel blocking actions are under study, obvious examples being derivatives of amiodarone that lack its toxicity.29

RSD1235 (52) is a compound currently in phase III clinical trials for intravenous use in the termination of acute onset atrial fibrillation. This compound is a mixed channel blocker with combined Class 1b and 3 effects. Blockade of IKur provides an atrial selective widening of action potential and this is combined with class 1b actions and a degree of ischemia dependency. This combination of electropharmacological properties probably accounts for the ability of RSD1235 to terminate AF while having minimal effects on the ventricle. The positive rate dependence probably confers selectivity for tachyarrhythmias and widens the therapeutic window in the treatment of AF RSD1235 showed no drug-induced arrhythmias or serious adverse events during phase I and phase II clinical trials.30 In a phase III trial, RSD1235 terminated AF without inducing torsades depointes (see later).

6.33.7.2.1 Combined class 1b and 3 actions

GYKI-16638 (57) (Figure 19) is one of a new series of N-(phenylalkyl)-N-phenoxyalkylamines, which combine the use dependent blockade of INa (Class 1b), with IKr and IK1 blockade. GYKI-16638 prolongs action potential duration in human ventricular muscle with little reverse rate dependence, unlike the typical selective IKr blockers.31 Such a neutral rate dependent effect, similar to amiodarone, is anticipated to lessen drug-induced proarrhythmia. Although GYKI-16638 is not a congener of amiodarone, it has certain structural similarities and might be expected to share some of the electrophysiological characteristics of amiodarone.

6.33.7.2.2 Combined class 3 and 4 actions

BRL-32872 (58) has blocking actions on both IKr and ICa with respective IC50 values of 0.028 and 2.8 mM. At low concentrations, with IKr blockade present, BRL-32872 prolongs action potential duration as expected of an IKr blocker, but at higher concentrations the ICa blockade becomes significant and counteracts the action potential prolonging effects. Moreover, BRL-32872 does not prolong action potential with reverse rate dependency, suggesting that ICa inhibition attenuates the undesirable reverse rate dependence of IKr block.32

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